However, Anx humans possess an ajd epiWAT Fat distribution and inflammation, which is disgribution related to inflammatlon of the metabolic syndrome dlstribution in later Immune support pills. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American heart association's strategic impact goal through and beyond. Such enhanced fuel mobilization is thought to be highest for visceral WAT Our findings support those of a previous study by Brochu et al. With much recent attention focused on BAT as a potential target for obesity treatment, it has recently been shown that BAT is an important effector organ in the glucose-lowering effects of metformin

Fat distribution and inflammation -

No relationship between fat distribution and resistin is also found in our study. In our results, the amount of IP fat was significantly positive correlated with hs-CRP and leptin but negative correlated with adiponectin.

IP fat may be inherently different from RP and SC fat, e. In conclusion, the findings of this study confirm that IP fat is a strong predictor of insulin resistance and metabolic syndrome in Taiwanese.

These observations reinforce the importance of treatment strategies designed to reduce IP part rather than RP part of visceral fat. Our results also suggest a relationship between IP adiposity and the chronic inflammation process.

This holds irrespective of age or other potential confounders, and was more prominent than the relationship between total obesity. It may be that, through the inflammation process and adipokines, a disproportionate accumulation of IP fat is associated with increased coronary risk. Hung KC: Obesity and its related diseases in Taiwan.

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Am J Physiol Endocrinol Metab. Download references. This work was supported by research grant CMRPG from Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Taiwan.

Department of Internal Medicine, Division of Endocrinology and Metabolism, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Ta-Pei Road, Niao- Sung Hsiang, Kaohsiung Hsien, , Taiwan.

You can also search for this author in PubMed Google Scholar. Correspondence to Ching-Jung Hsieh. P-WW, T-YC and C-JH collected data from their patients.

C-JH performed the data analysis and wrote the manuscript. All authors read and approved the final manuscript. This article is published under license to BioMed Central Ltd. Reprints and permissions.

Hsieh, CJ. The relationship between regional abdominal fat distribution and both insulin resistance and subclinical chronic inflammation in non-diabetic adults. Diabetol Metab Syndr 6 , 49 Download citation. Received : 23 July Accepted : 19 March Published : 01 April Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Objective Obesity is associated with a high risk of insulin resistance IR and its metabolic complications.

Methods There were volunteers without family history of diabetes mellitus and with normal oral glucose tolerance test enrolled. Conclusions IP fat is better predictors of IR and subclinical chronic inflammation in Taiwanese adults. Introduction The prevalence of obesity and overweight are still increasing globally.

Materials and methods Subjects There were volunteers enrolled to participate in the study. Methods Total body fat mass was measured by electrical bioimpedance analysis BIA , tetra-polar vertical BIA using 8-point tactile electrode InBody , BioSpace Inc.

Figure 1. Full size image. Results Study group characteristics are given in Table 1. Table 1 The characteristics of the study group Full size table. Figure 2. Table 2 Correlation between fat distribution and chronic inflammatory markers correcting for age and sex Full size table.

Discussion In this study, we found the relationship between regional abdominal adiposity and insulin resistance in a group of non-diabetic, middle-aged Taiwanese with varying degrees of body mass index. References Hung KC: Obesity and its related diseases in Taiwan.

Article Google Scholar Langenberg C, Sharp SJ, Schulze MB, Rolandsson O, Overvad K, Forouhi NG, Spranger J, Drogan D, Huerta JM, Arriola L, de Lauzon-Guillan B, Tormo MJ, Ardanaz E, Balkau B, Beulens JW, Boeing H, Bueno-de-Mesquita HB, Clavel-Chapelon F, Crowe FL, Franks PW, Gonzalez CA, Grioni S, Halkjaer J, Hallmans G, Kaaks R, Kerrison ND, Key TJ, Khaw KT, Mattiello A, InterAct Consortium: Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-InterAct case-cohort study.

Article PubMed Google Scholar Haffner SM: Abdominal adiposity and cardiometabolic risk: do we have all the answer?. Article CAS PubMed Google Scholar Bremer AA, Jialal I: Adipose tissue dysfunction in nascent metabolic syndrome.

Article CAS PubMed Google Scholar Tilg H, Moschen AR: Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Article CAS PubMed Google Scholar Rabe K, Lehrke M, Parhofer KG, Broedl UC: Adipokines and insulin resistance.

Article PubMed Central CAS PubMed Google Scholar Bu J, Feng Q, Ran J, Li Q, Mei G, Zhang Y: Visceral fat mass is always, but adipokines adiponectin and resistin are diversely associated with insulin resistance in Chinese type 2 diabetic and normoglycemic subjects.

Article CAS PubMed Google Scholar McLaughlin T, Lamendola C, Liu A, Abbasi F: Preferential fat deposition in subcutaneous versus visceral depots is associated with insulin sensitivity.

Article PubMed Central PubMed Google Scholar Usui C, Asaka M, Kawano H, Aoyama T, Ishijima T, Sakamoto S, Higuchi M: Visceral fat is a strong predictor of insulin resistance regardless of cardiorespiratory fitness in non-diabetic people. Article CAS PubMed Google Scholar Chowdhury B, Sjostrom L, Alpsten M, Kostanty J, Kvist H, Lofgren R: A multicompartment body composition technique based on computerized tomography.

CAS PubMed Google Scholar Abate N, Burns D, Peshock RM, Garg A, Grundy S: Estimation of adipose tissue mass by magnetic resonance imaging: validation against dissection in human cadavers. CAS PubMed Google Scholar Mårin P, Andersson B, Ottosson M, Olbe L, Chowdhury B, Kvist H, Holm G, Sjöström L, Björntorp P: The morphology and metabolism of intraabdominal adipose tissue in men.

Article PubMed Google Scholar Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM: Relationships of generalized and regional adiposity to insulin sensitivity in men. Article PubMed Central CAS PubMed Google Scholar Liew CF, Seah ES, Yeo KP, Lee KO, Wise SD: Lean, nondiabetic Asian Indians have decreased insulin sensitivity and insulin clearance, and raised leptin compared to Caucasians and Chinese subjects.

Article CAS PubMed Google Scholar Wulan SN, Westerterp KR, Plasqui G: Ethnic differences in body composition and the associated metabolic profile: a comparative study between Asians and Caucasians.

Article CAS PubMed Google Scholar Raji A, Seely EW, Arky RA, Simonson DC: Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians.

Article CAS PubMed Google Scholar Chang CJ, Wu CH, Chang CS, Yao WJ, Yang YC, Wu JS, Lu FH: Low body mass index but high percent body fat in Taiwanese subjects: implications of obesity cutoffs.

Article CAS PubMed Google Scholar Panagiotakos DB, Pitsavos C, Yannakoulia M, Chrysohoou C, Stefanadis C: The implication of obesity and central fat on markers of chronic inflammation: The ATTICA study.

Metabolically healthy obesity MHO vs. metabolically unhealthy obesity MUHO. In comparison with lean metabolically healthy subjects, those with MHO have increased adiposity and BMI, but with reduced systemic inflammation and retained insulin sensitivity, thus defining them as not having metabolic syndrome MetS.

MHO subjects have elevated subcutaneous white adipose tissue WAT levels, without excessive accumulation of visceral fat. Their adipokine profile is similar to lean subjects, but with increased leptin, resistin, and FGF21, and decreased adiponectin, which limits their risk of developing type 2 diabetes mellitus T2DM and cardiovascular disease CVD in the short term.

By contrast, those with MUHO exhibit elevated insulin resistance and systemic inflammation in addition to increased adiposity and BMI over lean controls, contributing to MetS.

MUHO individuals have excess subcutaneous and intra-abdominal adipose tissue, with increased hepatic fat and fat distributed amongst other visceral organs. This leads to a dysfunctional adipokine profile, characterized by reduced adiponectin and omentin, with further elevated leptin, resistin, FGF21, and cytokines when compared to lean controls.

Thus, MUHO subjects are at risk for developing T2DM and CVD. Notable differences in the adipokine profile between MHO and MUHO subjects have been reported, which could contribute to their respective risks for T2DM and CVD.

Leptin has been shown to be higher in MUHO than MHO obese Chinese children in one study , but was not found to differ between adult groups in several other studies — By contrast, adiponectin has consistently been shown to be higher in subjects with MHO than in those with MUHO, despite both populations having lower adiponectin than metabolically healthy lean controls , — Resistin and FGF21 levels tend to be highest in the MUHO population , Data on whether omentin levels differ between MHO and MUHO has been inconsistent, with one study suggesting that MUHO subjects have higher omentin levels than MHO subjects , and other suggesting the opposite, that omentin levels are negatively correlated with the metabolic syndrome , Cytokines such as TNFα and IL-6 as well as the chemokines SAA and MCP-1 have been shown to be elevated in MUHO These adipokine differences between subjects with MHO and MUHO are depicted in Figure 1.

Adipose tissue expansion in obesity is accompanied by inflammatory changes within adipose tissue, contributing to chronic low-grade systemic inflammation that is characterized as mildly elevated levels of circulating cytokines, chemokines, and acute phase reactants.

Expansion of adipose tissue depots during weight gain is accompanied by an infiltration of new inflammatory cells, the major one initially being macrophages. These pro-inflammatory cells are recruited in response to chemokines such as monocyte chemotactic protein-1 MCP-1 produced by hypertrophic adipocytes , Studies in mice have demonstrated that most macrophages in obese adipose tissue are derived from circulating monocytes , although a small percentage appear to derive from proliferation of resident tissue macrophages These anti-inflammatory macrophages are believed to be responsible for maintaining tissue homeostasis It remains unclear whether the derivation of adipose tissue macrophages is the same in human obesity.

Macrophage accumulation occurs to a greater extent in visceral than in subcutaneous adipose depots in both rodents and humans — Macrophages are seen in crown-like clusters, where they are thought to represent an immune response to dead and dying adipocytes However, use of genetic markers show that these cells have significant differences from classical M1 macrophages and alternate nomenclatures have been suggested for these pro-inflammatory cells.

Morris and Lumeng have divided adipose tissue macrophages into several populations based on cell surface markers and expression profiling Using a proteomics approach, Kratz et al. showed that markers of classical activation were absent on ATMs from obese humans.

Such markers of metabolic activation were expressed by pro-inflammatory macrophages in adipose tissue from obese humans and mice and correlated with the extent of adiposity In addition to macrophages, T-cells also are present in normal adipose tissue and demonstrate phenotypic change during weight gain.

Th2 cytokines e. With weight gain in mice there is a shift away from a predominance of TH2 T cells present in lean adipose tissue and toward more TH1 and cytotoxic T cells as well as a reduction in regulatory T cells Tregs Interferon γ IFNγ —expressing Th1 polarized T cells appear to promote adipose tissue inflammation and increased IFN-γ activity has been reported in adipose tissue in both mice and humans , A subset of T cells called natural killer T NKT cells respond to lipid or glycolipid antigens — The number of invariant NKT iNKT numbers has been observed to be reduced in adipose tissue and livers from obese mice and humans — B-cells and mast cells also are increased in adipose tissue in the obese state , , Use of specific cell surface markers has also demonstrated the presence of dendritic cells in adipose tissue, and studies indicate that dendritic cells are independent contributors to adipose tissue inflammation during obesity , There is good evidence to support the notion that the systemic inflammation that is associated with obesity and contributes to insulin resistance begins with adipose tissue inflammation.

The regulation of hepatic C-reactive protein CRP and serum amyloid A SAA is likely in response to IL-6 secretion from visceral adipose tissue that directly targets the liver via the portal circulation — CRP is a prominent biomarker for insulin resistance and CVD — , and SAA antagonizes insulin action in adipocytes, thus contributing to systemic insulin resistance SAA also has been associated with CVD in some rodent and human models , — In summary, the discovery of elevated secretion of inflammatory cytokines by obese adipose tissue provides evidence that obesity directly mediates systemic inflammation, which contributes to insulin resistance and CVD discussed further in later sections.

Obesity is associated with elevated circulating levels of IL-6 and TNFα, which are subsequently decreased with weight loss , Adipose tissue is a major source of these cytokines as well as the chemokine MCP-1, which is important for recruitment of inflammatory cells such as macrophages to expanding adipose tissue While such inflammatory mediators that originate from adipose tissue could technically be classified as adipokines, they are also produced by the majority of cell types in the body and will therefore be described in further detail in this section.

It should be noted that cytokine and chemokine production is limited in lean adipose tissue and in subjects with MHO. Many cell types synthesize and secrete these cytokines and chemokines, including several that make up the adipose tissue milieu such as monocytes, macrophages, dendritic cells, B cells, and T cells.

As such, they play a prominent role in adipose tissue pathophysiology associated with obesity. Much research has been devoted to the role that adipose-derived IL-6 plays in the etiology of obesity.

The expansion of adipose tissue is accompanied by excessive adipocyte lipolysis and subsequently elevated FFA levels, which promotes adipocyte IL-6 secretion , Omental fat produces 2 to 3-fold higher levels of IL-6 than subcutaneous fat , providing a potential mechanism for the higher contribution of omental WAT to insulin resistance Most studies in vitro and in mice suggest that adipose-derived IL-6 promotes hepatic insulin resistance and glucose intolerance , , , while some indicate that in certain contexts IL-6 signaling in WAT and liver may be protective against metabolic disease , For example, mice with genetic disruption of the IL-6 receptor specifically in the liver exhibit exacerbated hepatic inflammation and impaired glucose tolerance , suggesting that IL-6 may also function to limit hepatic inflammation.

Thus, the context in which IL-6 signaling is studied is critically important for the interpretation of its function. In addition to its secretion from inflammatory cells such as monocytes and macrophages, TNFα was first described as an adipokine in As with IL-6, TNFα levels positively correlate with adiposity, BMI, insulin levels, and insulin resistance , While adipocytes themselves can secrete TNFα, the majority of TNFα secreted from adipose tissue is derived from immune cells in the stromal vascular fraction, and that obesity-associated increases in TNFα largely reflect the infiltration of pro-inflammatory macrophages within expending adipose tissue One mechanism by which adipose-derived TNFα may promote insulin resistance is by directly activating hormone sensitive lipase HSL , thereby increasing FFA release from adipocytes which promotes insulin resistance in the liver and skeletal muscle Another mechanism is via autocrine activation of insulin receptor substrate-1 IRS-1 , which prevents insulin from interacting with its receptor Monocyte chemotactic protein-1 MCP-1 is a potent chemotactic factor that promotes monocyte and macrophage recruitment into sites of inflammation during tissue injury and infection.

It is secreted by adipocytes during the development of obesity and leads to infiltration of monocytes, which differentiate to become adipose tissue macrophages.

The macrophages in turn secrete additional MCP-1 leading to further recruitment of inflammatory cells , Body mass index and adiposity strongly correlate with adipose CCL2 the gene encoding MCP-1 expression levels, and MCP-1 decreases following weight loss in humans In addition, mice engineered to express elevated levels of Ccl2 specifically from adipocytes exhibit increased macrophage recruitment into adipose tissue, and subsequently increased insulin resistance, effects that were not observed in diet-induced obese mice that were deficient in Ccl2 Evidence suggests that human visceral WAT secretes higher levels of MCP-1 than subcutaneous WAT These studies and others have prompted the suggestion that MCP-1 could be a viable therapeutic target for the treatment of obesity and associated insulin resistance.

While well-described as an acute phase protein secreted by the liver in response to pro-inflammatory cytokines, SAA is also expressed in adipocytes and macrophages and correlates with adiposity , — There are 4 subtypes of SAA: SAA1—4. SAA1 and SAA2 are highly upregulated in response to inflammation, while SAA4 is largely constitutively expressed.

SAA3 is a pseudogene in humans, replaced by SAA1 and SAA2 in extra-hepatic tissues. While the best defined cell source of SAA1 and SAA2 is hepatocytes, SAA1 and SAA2 are also expressed from adipocytes and macrophages under inflammatory conditions in metabolic diseases such as obesity, insulin resistance, and cardiovascular disease SAA3 expression is increased during hypertrophy of cultured mouse adipocytes and in gonadal fat in obese mice , Inducible forms of SAA also are expressed in both subcutaneous and omental WAT from obese humans.

Thus, the increased adipocyte size and number that accompanies obesity is also associated with elevated adipose tissue-derived SAA levels, likely in part due to increased hepatic secretion in response to cytokines produced in adipose tissue. In obesity, white adipose tissue may become dysfunctional and unable to properly expand to store excess ingested energy, triggering storage of triglycerides in sites where the primary function is not fat storage.

Excessive amounts of visceral fat also is considered to be a form of ectopic fat, and as noted earlier, is associated with features of the metabolic syndrome and an increased risk of T2DM and cardiovascular complications In animal models as well as in humans, it has been shown that the accumulation of lipotoxic diacylglycerols DAGs and ceramide, as occurs with visceral obesity, leads to impaired insulin signaling and reduced glucose uptake in skeletal muscle and liver — More specific mechanisms by which ectopic fat accumulation in particular tissues promotes insulin resistance will be explained in the following sections.

Several studies have reported an inverse relationship between hepatic lipid content and whole-body insulin sensitivity — The liver is a major target for the excessively produced inflammatory cytokines and FFAs released from obese WAT see later. FFA-derived triglycerides accumulate in the cytoplasm of hepatocytes in the form of lipid droplets.

While the lipid droplets may not be lipotoxic per se , various intermediate lipid moieties generated during triglyceride synthesis e. Selective upregulation of ceramide degradation pathways in the liver has been shown to reverse hepatic lipid accumulation and improve glucose tolerance in diet-induced obese mice Moreover, obesity-associated reductions in adiponectin have also been shown to contribute to hepatic steatosis, presumably by blunting hepatic fatty acid oxidation, a process regulated by adiponectin — It also has been suggested that adipose tissue inflammation contributes to hepatic lipid accumulation.

Kanda et al. showed that overexpressing Ccl2 from adipocytes in mice led to macrophage accumulation in adipose tissue and subsequent hepatic steatosis and hepatic insulin resistance, without an obese phenotype Similarly, mice in which Ccl2 had been deleted showed resistance to high fat diet-induced insulin resistance and hepatic steatosis, an effect that was accompanied by reduced expression of TNFα in adipose tissue Additional evidence to support the notion that adipose tissue inflammation promotes hepatic steatosis derives from studies showing that adipose-derived cytokines promote lipolysis of WAT stores , , thus increasing circulating FFA levels.

In the healthy liver, the role of Kupffer cells is to phagocytose pathogens and toxins and to maintain tissue homeostasis and repair, akin to an M2 macrophage , The primary stimuli for Kupffer cell activation likely derive from dysfunctional adipose tissue, including FFA, cytokines, and adipokines Adipokine imbalance such as the hypoadiponectinemia that results from visceral adipose tissue expansion fails to suppress hepatic inflammation and oxidative stress, contributing to Kupffer cell activation.

Thus, signals from dysfunctional obese adipose tissue propagate hepatic inflammation by activating resident Kupffer cells, which then themselves secrete pro-inflammatory cytokines, further amplifying systemic inflammation Lipids also can be stored within skeletal muscle when the capacity for fat storage by WAT is exceeded Lipids can be stored either between muscle fibers as adipocytes, or extramyocellular lipids , or within muscle cells cytosolic triglycerides, or intramyocellular lipids Pre-adipocytes have been identified within skeletal muscle, providing evidence that distinct adipocyte cells may reside between skeletal muscle fibers There is an association between ectopic skeletal muscle fat and insulin resistance that is largely dependent on BMI, but this association persists when BMI is statistically accounted for — It remains to be determined whether skeletal muscle fat is simply a marker of metabolic dysfunction or if it plays an active role in mediating insulin resistance.

Ectopic skeletal muscle fat, as with ectopic fat in other areas, has the potential to impair insulin action in skeletal muscle through the inhibition of insulin signaling by lipotoxic DAGs and ceramide , Several large clinical trials including SECRET and CARDIA have recently suggested that skeletal muscle fat could play a direct role in increasing cardiometabolic risk — However, while ectopic fat in skeletal muscles is often associated with metabolic disease, highly trained athletes have been reported to have comparable amounts of skeletal muscle fat as subjects with T2DM, yet their tissue remains highly insulin sensitive Obesity and T2DM are both independently associated with fat accumulation in the heart , rendering ectopic fat in the heart as a strong predictor of CVD , , particularly in subjects with T2DM Similar to the liver, excess circulating FFA can also lead to increased triglyceride deposition in the heart.

Cardiac tissue mainly utilizes FFA for metabolism, but when delivered in excess of basal myocardial fatty acid oxidation rates can also lead to the accumulation of lipotoxic products In addition to ectopic cardiac myocyte lipid storage, excess FFA can be stored in epiWAT, pericardial fat between the visceral and parietal pericardia , or PVAT PVAT in particular has a major impact on vascular homeostasis.

As a source of several vasoactive mediators, PVAT influences vascular contractility. Healthy PVAT is thought to be a largely anti-inflammatory tissue , with characteristics akin to BAT in the areas surrounding the thoracic aorta in particular However, in the setting of obesity, dysfunctional PVAT releases predominantly vasoconstrictive and proinflammatory mediators that negatively influence vascular homeostasis — Similarly, epiWAT is a source of bioactive molecules that negatively impact cardiac rhythm and perpetuate an atherogenic environment in obesity Patients with T2DM express higher levels of the LDL and very low-density lipoprotein VLDL receptors in epiWAT than non-diabetic control subjects , suggesting that altered lipid metabolism in epiWAT could be associated with T2DM.

Recent studies have connected ectopic pancreatic fat with β-cell dysfunction and T2DM — , which in turn is associated with an increased risk of CVD. Therefore, lipotoxic lipid intermediates may also play a role in increasing the risk of CVD by elevating levels of pancreatic fat, thus leading to T2DM In contrast to skeletal muscle, ectopic pancreatic fat is characterized mostly by adipocyte infiltration rather than intracellular lipid accumulation The accumulation of fat in the pancreas also has been reported to accelerate acute pancreatitis due to increased levels of lipolysis and inflammation , Compared with healthy lean controls, obese subjects display reduced BAT content, identified as tissue that actively takes up 2-[ 18 F]fluorodeoxyglucose FDG This reduction in active BAT mass appears to be more prevalent in visceral obesity , Concurrently, individuals with detectable BAT activity display lower blood glucose, triglyceride and FFA levels, lower glycated hemoglobin Hb1Ac levels, and higher HDL cholesterol levels than people with no detectable BAT , Thus, loss of BAT function in association with obesity could contribute to the development of insulin resistance and hyperlipidemia.

It has been shown that while cold exposure can activate BAT to a certain degree in obese subjects and those with T2DM, the levels of BAT activation achieved are substantially lower than in healthy lean subjects , While BAT is largely resistant to the development of mild obesity-induced local inflammation, BAT inflammation becomes quite pronounced with stronger obesogenic insults Such inflammation can directly upset the thermogenic potential of BAT by impairing its ability to take up glucose described in more detail in later sections , Whether individuals who inherently possess less active BAT are more prone to obesity and facets of the metabolic syndrome or whether these pathological conditions themselves reduce BAT activity requires further investigation.

Regardless, it is still widely believed that strategies that augment BAT or beige activity could represent viable therapeutics to combat metabolic syndrome , Efforts to enhance BAT activation in humans consist of intermittent regular cold exposure, introduction of β 3 -adrenergic receptor agonists, and exercise 29 , However, robust reductions in body weight in humans have not yet been shown to be clinically significant when BAT is activated , necessitating further mechanistic studies to elucidate whether BAT activation is a viable target for metabolic improvement in humans.

Whether BAT undergoes similar immune cell changes as WAT under obesogenic conditions is still not clear. Such BAT inflammation reportedly lowers the thermogenic potential of this tissue , presumably due to increased local insulin resistance , , which could reduce the glucose and fatty acid oxidizing capacity of BAT.

Similar to BAT, beige adipocyte quantity and functionality appear to be sensitive to local inflammation. A study in which IkB kinase IKK, an enzyme that is required for NFκB activation and subsequent inflammatory cytokine transcription was inactivated in mice, not only blunted adipose tissue inflammation and body weight gain, but enhanced WAT browning Similarly, inhibiting a major intracellular mediator of toll-like receptor 4 TLR4 signaling, interferon regulatory factor 3 IRF3 , blunted WAT inflammation and augmented WAT browning Thus, accumulating evidence suggests that obesity-associated inflammation hinders the thermogenic and insulin sensitizing effects of both BAT and beige adipocytes.

Abundant evidence indicates that adiposity and adipose tissue inflammation are associated with insulin resistance, which refers to a reduced response to binding of insulin to its receptor in peripheral tissues such as adipose tissue and skeletal muscle.

This differs from glucose effectiveness, which is uptake of glucose by peripheral tissues in an insulin-independent manner. Insulin inhibits hepatic glucose output and stimulates lipogenesis in the liver, both of which are reduced in the presence of insulin resistance. Such desensitization of insulin signaling pathways also inhibits glucose uptake in peripheral tissues and stimulates lipolysis in adipose tissue.

To compensate for reduced insulin sensitivity, insulin secretion is increased in order to maintain euglycemia. If the pancreatic beta cells are unable to secrete sufficient insulin to compensate for the reduced insulin sensitivity termed beta cell dysfunction , hyperglycemia will ensue, leading to glucose intolerance and eventually T2DM While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier.

Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in 64 , ]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans.

Cross-sectional studies in men of European, Asian Indian, and American descent have shown that total, visceral, and subcutaneous adiposity, BMI, and waist circumference are all negatively associated with insulin sensitivity , As noted earlier, adiposity, especially visceral adiposity, is characterized by adipose tissue inflammation.

Several hypotheses have been put forth to account for the relationship between adipose tissue inflammation and insulin resistance. These include production of pro-inflammatory cytokines by adipocytes and adipose tissue macrophages discussed previously in the section on WAT Inflammation , excess FFA, decreased adiponectin, increased resistin and retinol binding protein, ceramide accumulation, and ectopic fat accumulation in liver and skeletal muscle It has been shown that adipose tissue mass correlates with circulating FFA in obese humans, with a tendency for individuals with visceral adiposity to have higher FFA turnover — It has also been reported that individuals with T2DM tend to have elevated FFA levels over non-diabetic controls , an effect found to correlate more strongly with insulin sensitivity rather than obesity Consistent with this, one study reported that FFA levels were lower in MHO subjects than those with MUHO In addition to dysregulated energy metabolism, disruption of the endocrine function of obese adipose tissue has now been shown to contribute to insulin resistance, described in more detail below.

Adipocytes in obesity simultaneously secrete lower levels of adiponectin and elevated levels of cytokines and chemokines, such as TNFα, IL-6, MCP-1, and SAA.

Not only is there evidence that such inflammatory cytokines contribute directly to insulin resistance in hepatocytes and myocytes , they also directly inhibit adiponectin production from adipocytes There is evidence that hypoadiponectinemia plays a role in obesity-associated T2DM — Subjects with T2DM exhibit reduced circulating adiponectin levels , ; similarly, MHO subjects have higher circulating adiponectin than those with MUHO This may be explained by the nature of adipose tissue expansion in these transgenic mice, which had smaller, less inflamed adipocytes and less liver fat content.

As discussed in earlier sections, FGF21 is a hormone produced by the liver as well as adipocytes that exerts insulin-sensitizing effects. However, recent evidence has paradoxically suggested an association between serum FGF21 levels and obesity-associated metabolic syndrome , FGF21 levels have been reported to be 2-fold higher in MUHO when compared to MHO Moreover, subjects with T2DM were reported to have significantly higher plasma levels of FGF21 than insulin-sensitive controls, with FGF21 levels positively correlated with BMI, HOMA-IR, and Matsuda index, suggesting a strong correlation with insulin resistance Plasma FGF21 levels also correlated strongly with visceral, epicardial, hepatic, and skeletal muscle ectopic fat levels, measured using slice multidetector CT scanning This conclusion was reached based on some observations that circulating FGF21 levels are increased in obesity, with lower FGF21 receptor expression levels on target tissues such as adipose tissue , However, this notion has been challenged by evidence that obese subjects are equally responsive to pharmacological administration of FGF21 , Thus, it has now been proposed that obesity-associated FGF21 is increased as a compensatory mechanism to preserve insulin sensitivity As such, a clear role for adipocyte-derived FGF21 in obesity and associated metabolic syndrome is still lacking.

Evidence suggests that ineffective adipose expansion promotes local inflammation and an insulin resistant phenotype However, sufficient adipogenesis and hyperplasia i.

Thus, strategies to increase the recruitment of adipocyte progenitor cells to expand adipose tissue by increasing adipose cell numbers could be protective against the metabolic consequences of obesity.

A key structural and functional component of adipose tissue is made up of extracellular matrix ECM molecules, including collagen and proteoglycans such as versican and biglycan, among others Adipose tissue makes large quantities of ECM during active remodeling, as would occur during WAT expansion in obesity — To date, most studies of WAT ECM function have centered around collagen, which can form a scaffold that constrains adipocyte expansion due to mechanical stress , , Targeting ECM components to release adipocytes from such constraints due to excessive ECM production could potentially alleviate the ectopic accumulation of fat that drives the metabolic syndrome.

While the majority of adipose tissue in humans is localized subcutaneously , the volume of visceral adipose tissue is believed to be a strong predictor of insulin resistance , independent from subcutaneous fat quantity , The association between insulin resistance and visceral adipose mass is particularly striking in certain ethnic populations, with T2DM rates of While visceral adiposity is positively associated with insulin resistance, there is evidence to suggest that it may not be a causal factor.

Other conditions associated with visceral adiposity, such as hepatic fat content, may instead drive insulin resistance , Some clinical studies have dissociated the glucose metabolic effects of visceral adiposity from hepatic lipid accumulation. In one such study, significant differences in insulin sensitivity in the liver, skeletal muscle, and adipose tissue were reported in obese human subjects who differed in hepatic lipid content, with no such differences observed in obese subjects who differed in visceral adiposity Similarly, in a study in which obese subjects were matched for liver fat content, no differences in indices of glucose metabolism were noted Insulin-sensitive MHO individuals tend to have lower visceral and intrahepatic fat accumulation than their MUHO counterparts , , , providing further evidence that these fat depots contribute to insulin resistance.

Collectively, while visceral adiposity and hepatic fat content are both strongly associated with whole-body and tissue-specific insulin resistance, hepatic lipid accumulation may play a more direct role in negatively modulating glucose homeostasis. Many studies have suggested that fat distribution is strongly associated with insulin resistance, with visceral adiposity being the strongest predictor of insulin resistance , , While the detrimental effects of visceral and hepatic lipid accumulation on glucose metabolism are clear, it is also becoming increasingly appreciated that lower body subcutaneous adiposity may be metabolically protective — Large-volume liposuction of subcutaneous WAT has shown little to no metabolic benefit in human trials Gluteofemoral adipose mass is positively associated with insulin sensitivity in humans, coupled with a slower rate of lipolysis and subsequent FFA release, lower levels of inflammatory cells and cytokines, and elevated adipokines such as leptin and adiponectin Evidence from animal models has suggested that transplantation of subcutaneous WAT into the visceral cavity of recipient mice promotes less body weight and adiposity gain than transplantation with visceral WAT, resulting in greater insulin sensitivity in the liver and endogenous WAT Taken together, a growing body of evidence suggests that adipose tissue and ectopic lipid distribution contribute to whole-body glucose homeostasis.

With the purported potential to improve glucose homeostasis, interest in BAT and beige adipose tissue as therapeutic targets has increased in recent years.

Studies in rodents in which BAT is transplanted into diseased mouse models have shown that transplanted BAT improves insulin sensitivity, glucose metabolism, and obesity — , likely mediated by batokine effects.

As a highly metabolically active organ, BAT contributes to glucose clearance by taking up relatively large amounts of glucose from the circulation, thus reducing insulin secretion by pancreatic β-cells Indeed, individuals that possess detectable BAT have lower fasting glucose concentrations than those without active BAT Glucose disposal through activated BAT occurs by both insulin-dependent and insulin-independent mechanisms For example, the cold exposure-mediated influx of glucose into active BAT has been suggested to be an insulin-independent process — However, as the insulin receptor is highly expressed in BAT tissue, it is considered to be one of the most sensitive insulin target tissues and thus an important organ for glucose disposal BAT activation further enhances insulin signaling in BAT itself by augmenting insulin-independent glucose uptake associated with thermogenesis and glucose uptake due to insulin signaling.

Thus, strategies that activate BAT and beige adipose tissue have the capacity to improve insulin resistance by clearing excess glucose — Several pathologic conditions, including hypercholesterolemia and systemic inflammation, are hypothesized to drive atherosclerotic CVD.

With a primary function of sequestering lipotoxic lipids and the known potential for chronic inflammation, obese adipose tissue has emerged as a potential player in the regulation of these atherogenic factors.

Obesity has been officially classified as an independent risk factor for CVD by the American Heart Association since , meaning that obesity treatment is likely to lower the incidence of CVD As alluded to in previous sections, people with MHO are at a lower risk of experiencing cardiovascular events than people with MUHO , yet those without obesity are at a considerably lower risk for future events.

Thus, even a moderate level of weight loss, if sustainable, could potentially lower the risk of adverse CVD events Possible reasons include confounding factors such as smoking and the presence of co-morbidities that are associated with lower body weights, or the use of BMI rather than measures of visceral obesity for most studies on the obesity paradox.

Despite the obesity paradox in those with established CVD, the following sections will provide information regarding potential links between obesity T2DM and CVD. The various features of adipose tissue depots, including ectopic fat, and how they contribute to T2DM and CVD are summarized in Figure 2.

Notably, there are many similarities between adipose depot characteristics that contribute to both T2DM and CVD. Figure 2. Adipose depots and ectopic fat sites and their features that contribute to type 2 diabetes mellitus T2DM or cardiovascular disease CVD. Features of intra-abdominal white adipose tissue WAT , subcutaneous fat, hepatic fat, heart and arterial fat inclusive of epicardial, pericardial, and perivascular fat , pancreatic fat, skeletal muscle fat, brown adipose tissue, and a dysbiotic gut that contribute to either T2DM or CVD.

Arrows indicate changes in comparison with subjects without T2DM or CVD. The accumulation of visceral fat in obesity is associated with the metabolic syndrome, its associated CVD risk factors, and an increased risk for clinical CVD This distribution of WAT has been shown to have the greatest effect on CVD risk and mortality among patients with normal body weight The risk of CVD in the metabolic syndrome has been considered to result from the presence of multiple CVD risk factors such as dyslipidemia hypertriglyceridemia, an excess of small, dense LDL particles and reduced HDL-cholesterol levels , hypertension, dysglycemia, and a thrombogenic profile that have been reviewed elsewhere — However, there are several additional potential mechanisms by which visceral WAT might contribute directly to CVD that involve FFA, insulin resistance, and inflammation.

Visceral WAT has higher lipolytic activity than subcutaneous WAT due to its having fewer insulin receptors, and thus is a significant source of FFA. Visceral-derived FFA can directly impact the liver via the portal vein, facilitating FFA uptake by the liver and subsequent hepatic insulin resistance.

Similarly, excess FFA from visceral fat might directly impair lipid metabolism and lead to dyslipidemia, which increases CVD risk. In obese diabetic subjects, plasma FFA levels have been shown to be elevated compared to BMI-matched non-diabetic subjects , supporting the notion that insulin resistance further elevates circulating FFA levels.

Moreover, the incidence of T2DM is nearly doubled in patients with the highest levels of FFA 90th percentile when compared with subjects with the lowest FFA levels 10th percentile In one study, obese T2DM subjects who had undergone overnight fasting during pharmacological inhibition of lipolysis exhibited improved insulin sensitivity and glucose tolerance , providing further evidence for an inhibitory effect of FFA on insulin sensitivity.

The adipokine profile of visceral WAT also contributes substantially to its association with CVD risk. Obese visceral WAT primarily secretes inflammatory cytokines such as resistin, TNFα, IL-6, IL-1β, MCP-1, and SAA, with reduced levels of adiponectin Plasma adiponectin levels are decreased in patients with CVD Adiponectin is believed to contribute to CVD protection by several mechanisms, including the reduction of lipid levels, repressing expression of inflammatory mediators such as VCAM, ICAM, E-selectin, TNFα, and IL-6, and by acting directly on the heart to improve ischemic injury by activating AMPK and subsequently increasing energy supply to the heart — Adiponectin also stimulates endothelial nitric oxide synthase eNOS , which maintains healthy vascular tone , Thereby, adiponectin would play a protective role in the development of CVD.

Conversely, leptin levels are positively associated with acute myocardial infarction, stroke, coronary heart disease, chronic heart failure, and left cardiac hypertrophy — , although the reasons for this remain largely unknown.

Leptin receptors are expressed in the heart, indicative of an important impact of direct leptin signaling Resistin is positively associated with systemic inflammatory markers , upregulates endothelial expression levels of VCAM-1 and endothelin-1 and promotes the proliferation of smooth muscle cells Resistin also associates positively with coronary artery calcification levels, and negatively with HDL cholesterol Thus, adipose-derived resistin levels could be used to predict the severity of coronary atherosclerosis Similarly, cytokines and chemokines such as those secreted from obese visceral WAT can induce expression of endothelial adhesion molecules , recruit macrophages , increase thrombosis , and reduce vasoreactivity , and are positively associated with cardiovascular events , While visceral WAT-derived cytokines are associated with these CVD-inducing processes, it is important to note that the direct contribution from visceral WAT is not currently known, as these are also secreted from other tissues.

As discussed in previous sections, in addition to cytokines and exclusive adipokines, WAT is also a source of FGF While the liver is considered to be the major source, adipocytes have also been shown to produce FGF21 to varying degrees in response to various stimuli.

In addition to its associations with obesity and T2DM, FGF21 levels have also been associated with increased risk for CVD — Subjects with CVD that also had diabetes exhibited even higher levels of FGF21 , suggesting an important role in diabetes-accelerated atherosclerosis.

In particular, FGF21 levels have been shown to positively correlate with hypertension and triglyceride levels, and to negatively correlate with HDL-cholesterol levels One study by Lee et al.

suggested that plasma FGF21 levels are associated pericardial fat accumulation , which suggests that ectopic fat could be a source of FGF21 in metabolic disease. Further studies are needed to discern whether adipocyte- or hepatic-derived FGF21 contribute to these effects.

In stark contrast to these effects of physiological FGF21, pharmacological administration of FGF21 in humans and non-human primates reduces blood glucose, insulin, triglycerides, and LDL cholesterol, and increases HDL cholesterol , , Thus, there is a disconnect between the physiological and pharmacological effects of FGF21 that requires further study.

It is becoming increasingly clear that adipose tissue expansion contributes directly to obesity-associated cardiovascular disease risk Obesity is accompanied by not only excess visceral adiposity, but also by excess epicardial and perivascular WAT Due to their proximity to the heart, coronary arteries, and other major arterial blood vessels that are prone to atherosclerosis, it is not surprising that epiWAT and PVAT are important regulators of cardiac and vascular.

The respective sizes of these adipose depots are associated with risk factors for the metabolic syndrome, including elevated visceral fat content, blood glucose, hypertension, systemic inflammation, insulin resistance, circulating LDL levels, mean arterial pressure, and atherosclerosis 19 , — , as well as adverse cardiovascular events — The mechanisms behind these associations include increased secretion of pro-inflammatory cytokines, vasoactive factors, and vascular growth factors — ; increased release of lipotoxic FFA , ; increased macrophage content ; increased oxidative stress ; and decreased secretion of adiponectin , which are triggered by obesity.

In a prospective cohort of patients with aortic stenosis, a positive association between epiWAT volume and left ventricular mass was found , suggesting that in addition to changes in adipokine secretion, epiWAT could negatively influence cardiac function by placing a restrictive burden on the heart.

Mechanisms by which PVAT influences CVD are more nuanced and complex. As an adipose depot that features some characteristics of both WAT and BAT, and with different functions depending on the anatomical location i. abdominal aortic PVAT , PVAT can play either a cardioprotective or a pathological role As obesity progresses, PVAT can become dysfunctional in that it more resembles WAT, and contributes to a pro-inflammatory and lipotoxic microenvironment that promotes atherosclerosis Thus, while PVAT and BAT play atheroprotective roles in healthy individuals, obesity promotes dysfunction of these depots, blunting this protective effect against CVD.

Strategies for weight loss are multi-faceted, including combinations of diet and lifestyle modifications, pharmaceutical therapy, and various forms of bariatric surgery While there is some debate over this, it is generally believed that small degrees of weight loss in MUHO obese populations can have a dramatic impact on cardiometabolic health , ; thus, strategies that improve obesity are likely to also decrease risk factors for CVD.

Similarly, CVD treatment strategies are centered around a combination of pharmaceutical use and lifestyle modifications, which also impact adipose tissue. In this section, we will describe the effects that various CVD treatment strategies have on adipose tissue metabolism and inflammation.

How these treatment strategies impact the contributions of particular adipose depot features to T2DM and CVD are listed in Figure 2. Traditional methods prescribed for weight loss include restricting food intake and increasing energy expenditure.

Despite a large number of fad diets that dictate particular proportions of dietary fat, protein, and carbohydrates to facilitate weight loss [summarized in , ], the simple fact remains that for weight loss to occur, energy balance must be negative.

Thus, energy intake must be less than energy expended, which includes resting energy expenditure, physical activity, and the thermic effect of food. Subsequently, additional studies have shown that modest weight loss due to dietary changes in people with overweight or obesity is due to roughly equivalent fat lost from subcutaneous and visceral depots, while the addition of exercise leads to more weight loss from subcutaneous fat as well as loss of ectopic skeletal muscle fat — The loss of visceral fat is associated with reduced CVD risk factors, including reduced systemic inflammation, total cholesterol, LDL cholesterol, and triglycerides , , as well as reduced fasting glucose and insulin levels , As the subjects recruited for the Look AHEAD trial had T2DM, this and other post-hoc analyses suggest that weight loss in T2DM subjects also lowers the risk of CVD events , It is well established that aerobic exercise increases fuel mobilization from adipose tissue by increasing lipolysis and subsequent FFA mobilization, which ultimately decreases adiposity and adipocyte size — Such enhanced fuel mobilization is thought to be highest for visceral WAT Hepatic fat is also mobilized and decreased following intense aerobic exercise Studies in mice suggest that not only visceral fat mass is lost with regular exercise, but subcutaneous and brown fat mass are also diminished As expected with fat loss, exercise is coincident with reduced plasma and adipose tissue leptin levels — The effects of exercise-induced fat loss on adiponectin levels are less clear, with some studies showing no changes in circulating adiponectin levels — , some showing increased plasma adiponectin — , and others showing increased subcutaneous WAT expression of adiponectin mRNA — A meta-analysis showed that pediatric subjects with obesity exhibit reduced resistin levels following aerobic exercise Little is known about the impact of exercise on FGF21 in obese humans, but one study suggested that aerobic exercise training in obese women reduced circulating FGF21 levels By contrast, studies in rodents have shown that circulating FGF21 levels are not altered by exercise in obese animals Collectively, such exercise-induced changes to WAT distribution and adipokine secretion likely facilitate the observed improvements in insulin sensitivity and CVD risk factors observed with exercise.

While many studies have reported that exercise training increases subcutaneous WAT browning in rodent models of obesity — , there is limited data to support this in humans.

Many studies have shown that there is no effect of aerobic exercise training to recruit beige adipocytes in humans However, one study compared subcutaneous WAT from lean, sedentary young men with age- and weight-matched endurance-trained men and reported no differences in beige markers such as UCP1, PGC1A , or CIDEA Another study found evidence of subcutaneous WAT browning i.

There is some debate about what role brown or beige adipose tissue would play in exercise, if it indeed occurs. Exercise is known to activate the sympathetic nervous system, which also activates BAT to quickly release stored energy, so it is possible that BAT activation is secondary to exercise-induced sympathetic activation Loss of adipose tissue mediated by dietary changes, exercise, liposuction, or bariatric surgery discussed in the section on Bariatric Surgery is accompanied by decreased markers of adipose tissue and systemic inflammation , Fat loss by liposuction yielded similar changes in systemic inflammatory markers in one study , but did not improve plasma cytokine levels in another The removal of visceral fat from Zucker diabetic fatty rats resulted in dramatic reductions in systemic cytokines ; this suggests that removing visceral fat, rather than the subcutaneous fat that is routinely removed during liposuction, is more advantageous in terms of resolving inflammation.

Many studies also have shown that weight loss following bariatric surgery leads to reductions in systemic inflammatory markers , with notable reductions in adipose tissue inflammatory cytokine and macrophage expression — However, some similar studies do not show improvements in adipose tissue inflammation following various weight loss modalities, such as bariatric surgery or very low-calorie diets — It has been suggested that pronounced weight loss over time can lead to improvements in adipose tissue inflammation that were not observed in the same subjects following acute moderate weight loss This implies that adipose tissue inflammation during the initial stages of weight loss could be required for the pronounced adipose tissue remodeling required for fat loss , Metformin is the most commonly prescribed medication to treat T2DM, particularly in subjects with obesity Metformin has been proposed to lower blood glucose levels through suppression of gluconeogenesis in the liver, activation of AMP-activated protein kinase AMPK , inhibition of the mitochondrial respiratory chain complex 1 , and by unknown mechanisms in the gut , Thus, the precise mechanisms by which metformin lower blood glucose are complex and still evolving.

While some diabetes medications have adverse effects on body weight, patients taking metformin often lose a small amount of weight [reviewed in ]. Studies in T2DM suggest that metformin may reduce body fat stores and promote a more metabolically healthy fat distribution — The effect of metformin on adiposity may be partially due to reported nausea and anorexic effects of the drug — With much recent attention focused on BAT as a potential target for obesity treatment, it has recently been shown that BAT is an important effector organ in the glucose-lowering effects of metformin Some studies have reported increases in omentin following metformin therapy, which could be due to visceral fat loss Metformin also reduces hepatic steatosis through inhibition of ApoA5 and steroyl-CoA desaturase-1 SCD1 which combine to limit de novo lipid synthesis, which is partially mediated by its actions on AMPK and liver X receptor LXR activity , It also has been suggested that metformin reduces ECM remodeling that is dysregulated in obesity see previous section on adipose tissue plasticity , and reduces lipogenesis In addition to the increasingly recognized anti-obesity effects of metformin, its ability to improve CVD risk is also becoming apparent The mechanism may include improvements in the lipid profile, such as mild reductions in plasma VLDL cholesterol and triglycerides with slight elevations in HDL cholesterol In addition, metformin has been shown to have anti-inflammatory properties, reported to reduce circulating CRP and MCP-1, reduce NFκB activity, and to reduce advanced glycation end products AGE — Glucagon-like peptide-1 GLP-1 is a peptide hormone that is continuously secreted at low levels during fasting by intestinal L cells.

Consumption of a meal enhances GLP-1 secretion, which functions to reduce plasma glucose levels by stimulating insulin secretion from pancreatic beta cells. In addition, GLP-1 receptors are abundant in brain areas that control food intake regulation, such as the hypothalamus, where GLP-1 functions to reduce the drive to eat , Thus, several GLP-1 receptor agonists have been developed to mimic the glucose-lowering and anorexic effects of GLP-1 to treat obesity and T2DM.

Liraglutide, a GLP-1 receptor agonist, has shown efficacy in not only glucose control, but also in promoting weight loss and reduced waist circumference based on results from the Liraglutide Effect and Action in Diabetes LEAD study — Liraglutide has also been shown to reduce total adiposity, and specifically visceral fat mass , While initially described as being devoid of GLP-1 receptors , it has now been confirmed that adipocytes express the GLP-1 receptor , Adipose tissue may therefore be an additional target for GLP-1 receptor agonists to promote adipose remodeling by unknown mechanisms.

In addition to its effects on body weight and glucose metabolism, GLP-1 receptor agonists may also provide protection against CVD The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER trial showed that liraglutide lowered the risk of myocardial infarction and non-fatal stroke among patients with T2DM that had high CVD risk GLP-1 receptor agonist treatment has been shown to protect against atherosclerosis in animal models and in humans, potentially by lowering plasma lipids and by reducing circulating CRP and soluble ICAM-1 levels — Liraglutide, when administered in combination with metformin as indicated for the treatment of T2DM, has been shown to reduce epicardial WAT volume with simultaneous increased omentin expression Thus, liraglutide may provide cardioprotection through reduced levels of ectopic fat, lipids, and inflammation.

Inhibitors of the sodium-glucose cotransporter 2 SGLT-2 have been shown to reduce blood glucose levels in subjects with T2DM by enhancing urinary glucose excretion The SGLT-2 inhibitor empagliflozin, alone and in combination with the GLP-1 receptor agonist liraglutide, has been shown to reduce CVD risk , as well as cardiovascular death to a greater extent than statins alone Empagliflozin also is associated with decreased hypertension, reduced arterial stiffness, and decreased vascular resistance , In both rodents and humans with non-alcoholic fatty liver disease, SGLT-2 inhibitors have been shown to reduce ectopic liver fat by blunting de novo hepatic lipogenesis — , with reduced alanine transaminase ALT and aspartate transaminase AST levels , two markers of hepatic metabolic stress.

Furthermore, empagliflozin is associated with weight loss in humans when administered in combination with other therapeutics, such as metformin, thiazolidinediones, and sulfonylureas — In rodents, SGLT-2 inhibitors have been shown to suppress high fat diet-induced weight gain and to markedly reduce obesity-induced inflammation in WAT, potentially by increasing fat oxidation and the recruitment of beige adipose tissue , Thus, in addition to correcting hyperglycemia, SGLT-2 inhibitors can also impact adipose tissue physiology; whether this is through direct or indirect mechanisms remains to be elucidated.

For inflammatioj information about PLOS Subject Areas, click here. Fat distribution and inflammation is Immune support pills growing problem distrlbution, especially in countries with improved socioeconomic circumstances. Also, in the Netherlands the incidence of overweight and obesity is rising. There is increasing evidence on the association between obesity and tumorigenesis. Of all cancer types, endometrial cancer EC has the strongest positive correlation with obesity.

For more information about Inflammatuon Subject Areas, click here. Obesity is a growing problem worldwide, especially in countries with anv socioeconomic circumstances.

Also, in the Netherlands the anx of distributon and obesity is rising. There is increasing inflammqtion on the association between obesity lnflammation tumorigenesis. Of all cancer diatribution, endometrial cancer EC has the strongest inflammatipn correlation with obesity.

Visceral fat is assumed inlammation be relatively more distribtuion active and likely negative Far biomarker in non-endometrioid EC.

Whereas subcutaneous fat is mainly responsible for distriibution production through increased Diabetes complications coma activity. The aim of znd study disfribution to compare hormone levels and inflammatory markers after Breathing exercises for stress reduction salpingo-oophorectomy BSO in obese and non-obese patients.

Secondary Control cravings for unhealthy desserts Immune support pills to Distributiom the effect inflammarion fat distribution and diagnosis benign vs. EC Immune support pills the observed changes in Fat burner supplements levels and inflammatory markers, and to compare the effect of Distributioj Immune support pills menopausal complaints.

Prospective multicentre observational cohort study. Preoperative disgribution CT will be performed and fasting venous blood samples are obtained distdibution hormone levels and inflammation markers analysis.

Fat distribution and inflammation surgery, adipose tissue biopsies of inflammatuon Immune support pills visceral omental and intestinal aand fat distrribution will be collected and stored fresh ditsribution. In addition a fasting blood draw six weeks after surgery will be obtained.

All disgribution will fill in dkstribution questionnaires before surgery and one after surgery. Distributiion hypothesize that BMI, the Fag of fat distribution, Immune support pills, and Ac self-testing devices the underlying pathology significantly Astaxanthin and acne treatment in hormone inflammaiton, and systemic infammation changes after BSO.

Previous studies Healthy skin tips Immune support pills several clues idstribution a relationship between inflamation and endometrial cancer. Citation: van den Bosch AAS, Pijnenborg JMA, Romano A, Distribuyion IS, Werner HMJ The inflwmmation of High-fiber foods distribution and inflammation in the origin inflamnation endometrial inflammation, study protocol of Dark chocolate sensation ENDOCRINE study.

PLoS ONE 17 10 : e Received: July 13, ; Accepted: September infalmmation, ; Published: October 27, Copyright: © van den Bosch an al. This is distribuhion open access distdibution distributed under the terms of the Distributipn Commons Attribution Licensewhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author inflammagion source are credited.

Data Availability: No annd were generated or analysed during the inflammztion study. All relevant data from this study will be made available inflammatino study completion.

The sponsors infla,mation have Faat roll in the study inflammayion, data adn or ristribution of cistribution manuscript. Competing inflamation Fat distribution and inflammation authors have disttibution that no competing interests exist.

Obesity is a growing problem worldwide, inflammafion in countries inflammwtion socioeconomic circumstances improve djstribution 1 inlammation.

In the Netherlands the incidence of overweight and obesity is rising [ 2 inflammtion. Obesity is related ahd many diseases, including diabetes and Stress management for better mental health disease Fqt 3 Wound healing ointments, 4 ], there Immune support pills distributjon increasing evidence on the association between obesity and tumorigenesis.

The Faf mechanisms linking obesity to cancer distribtuion are complex and Distributin not be distributuon in infammation tumour types distfibution 5Fat intake effects ].

There disyribution three main hypotheses inflammafion obesity to the ibflammation of cancer. Considering all cancer types, inflaammation cancer EC incidence Fat distribution and inflammation the strongest positive correlation inflammatoin BMI [ 7 — 9 ]. In Innflammation, long-term unopposed infpammation stimulation has been inflammatiin to play a distribtuion role, especially in the aetiology of the endometroid subtype.

Adipose tissue inflwmmation a very complex anf organ inflammatiom produces adiponectin, Fst, and also steroid hormones. In premenopausal women the ovaries are the main source of oestrogen production [ 10 distribjtion 12 ]. However, after menopause, the subcutaneous adipose tissue distribuhion the ahd important infpammation of oestrogens due to the presence of aromatase, which converts androgens to disttribution [ 13 ].

Menstrual health experts mechanism unflammation the production of endogenous sex-steroids plays an important role in the development anc EC. Furthermore, obesity-mediated dustribution and insulin FFat have also shown to be important in this process [ 5614 ].

Chronic hyperinsulinemia, which is common in obese women, has an inflammatioj on cell proliferation directly by high insulin levels and indirectly by higher levels of circulating insulin growth factors IGFs. The chronic inflammation in obese patients results in a higher level of leptin anti-apoptotic and pro-angiogenetic and a lower level of adiponectin which as a result promotes cell proliferation and inhibits cell death.

These three mechanisms are thought to play an important role in the development of EC [ 45 ]. The chronic hyperinsulinemia and systemic inflammation possibly also explains why also for the non-endometrioid subtype, the incidence rate is positively associated with weight gain [ 1516 ].

BMI is a simple, and clinically easily applicable Ft, yet does not cover the complexity of fat distribution in visceral- and subcutaneous compartments, nor the ratio between muscle tissue and fat tissue [ 1618 ]. Internationally the importance of fat distribution is gaining more attention [ 19 — 21 ].

Previous study showed that a higher visceral fat percentage was a negative prognostic biomarker in non-endometrioid EC NEEC [ 19 ] compared to subcutaneous fat which is important for oestrogen production through increased aromatase activity [ 202223 ].

Fat distribution can be measured by imaging methods like CT and MRI or estimated by measurements of skinfolds, DXA-scan and hip-waist circumference.

The latter divides women into two groups, women with an apple figure who presumably have more visceral fat and women with a pear figure who most likely have more subcutaneous fat.

The MRI an CT related measurements can distinguish between subcutaneous and visceral adipose tissue [ 5 ]. Adipose tissue compartments, determined by CT segmentation scans, have been correlated to systemic hormone levels, tumour inflammation and pathway activation in a number of studies [ 19 — 22 ].

In the light of the differences between adipose tissue in the various compartments, the relative increase in central obesity visceral obesity through the menopausal transition is of potential additional importance [ 24 ]. Through the rising prevalence of obesity worldwide, it is expected that the EC incidence will continue to rise [ 1152526 ].

In the more affluent countries, EC is the most frequent gynaecological malignancy [ 2728 ]. The primary treatment of EC consists of hysterectomy with BSO. Removal of ovaries serves three goals: 1, it is part of the staging procedure of EC; 2, to exclude the chance of concurrent ovarian cancer and 3, it leads to reduction of the remaining oestrogen and androgen production and thus possibly reduces risk of recurrence.

It is uncertain to what extent the sex steroid hormone and inflammatory levels drop after BSO, especially in obese women with endometrial cancer.

Removal of the ovaries demonstrates to what extent oestrogen production is or was driven by the ovaries dlstribution the adipose tissue compartment.

Pinpointing this more specifically will help in further understanding the role of adipose tissue in the development of EC. This is a prospective observational cohort study. Patients will be recruited from four hospitals including two academic hospitals academic hospital Maastricht AZM and Radboud university medical centre Radboudumc and two large teaching hospitals Canisius Wilhelmina Ziekenhuis CWZ and Distrinution.

Inclusions started from 1st of September in Inflammmation and Radboudumc and inclusions at CWZ and VieCuri will start in As of this moment the study is actively recruiting. All participants will provide written informed consent. The aim of this study is to compare hormone levels and inflammatory markers after BSO in obese and non-obese patients.

endometrial cancer on changes in hormone levels and inflammatory markers after BSO in obese and non-obese patients, and to compare the effect of BSO on menopausal complaints. We hypothesize that obese post-menopausal women will still have relatively high circulating concentration of oestrogen, especially women with a high subcutaneous fat percentage.

Total number of participants is women. Patients will be included pre-operatively. In case of a final diagnosis being ovarian malignancy, this participant will be excluded and a patient with a benign diagnosis included instead.

There are no previous studies with comparable analysis, allowing for a formal sample size calculation. Therefore, we have taken the difference in hormone level as the starting point for a sample size calculation.

We have chosen to include onflammation, 80 obese and 80 distrribution. Three time points for patients with benign disease T1-T3 and four time points T1-T4 for patients with endometrial cancer EC. At three women with benign diagnoses or four women with EC different time points data will be collected from the subjects.

At timepoint 1 T1a physical examination is conducted where hip and waist circumference are measured and patient variables including age, height, weight, BMI, history, cumulative illness rating scale CIRS and menopausal status collected.

Furthermore, routine abdominal CT imaging will be performed in all patients. Finally, patients are requested to answer a validated questionnaire, the Green climacteric scale enquiring into presence of menopausal symptoms, and are asked to answer three questions on their physical activity level.

At timepoint 2 T2 subjects will undergo the clinically indicated surgical procedure. At start of surgery, a fasting blood draw will be obtained to measure oestrogen levels and systemic inflammation markers.

During surgery subcutaneous adipose tissue and visceral adipose tissue fat apron and intestinal epiploic fat as well as tumour where applicable will be collected, and snap frozen. At timepoint 3 T3 4 to 6 weeks postoperatively, another fasting blood draw is obtained for measurement of oestrogen levels and systemic inflammation markers.

In case of a recent infection the blood draw will be postponed until 10 days after the end of the infection. In case of adjuvant therapy, the postoperative blood draw will be performed latest at start of the adjuvant therapy.

Finally, subjects will be asked to fill in the Green climacteric scale questionnaire a second time. For subjects with the diagnosis of EC clinical follow-up data will be collected during 3 years T4. Using the abdominal CT-scans, abdominal fat volumes will be segmented and quantified using a semi-automatic dedicated software iNtuition, TeraRecon Inc.

San Mateo, CA, USA [ 2030 ]. The biospecimens will be temporarily stored prior to use in this study at the MUMC Biobank [ 31 ]. In the Biobank Information System BIS type, date and volume of each specimen is recorded.

A selection of steroid hormones including oestrogens, androgens, progestogens and corticosteroids as well as local adiponectin, resistin, leptin will be determined in the collected adipose tissue.

Inflammatory markers both locally in fat tissue macrophages, T cells: TNF-α, IL-6, and IL-1β and systemically blood including C-reactive protein CRPinterleukin 1 beta IL1βinterleukin 6 IL6tumour necrosis factor alpha TNFαinsulin-like growth factor 1 IGF1will be determined.

Samples will be further characterised by omics technologies genomics, transcriptomics, proteomics and metabolomics. Generated data will be used for biomarker discovery, this data will be used to explore the cellular pathways underlying the various patient characteristics.

Pre- and postoperative questionnaires will be analysed and compared. The Green climacteric Scale, assessing menopausal complaints, can be divided into three subcategories; psychological, physical and vasomotor complaints [ 32 ].

We will assess all three subcategories separately to evaluate if there are any differences in the groups of patients pre vs. postmenopausal and obese vs. non-obese patients. Using a population-based inclusion, we would likely have too low numbers in some groups to allow for meaningful analyses.

However, as a consequence the external validity is somewhat reduced.

: Fat distribution and inflammation

The relation of body fat mass and distribution to markers of chronic inflammation	Goodpaster, Distribuhion Ferrucci, Tamara Diztribution. C-reactive Nutritional tips for weightlifters and other markers of inflammation in the Immune support pills of cardiovascular disease Fat distribution and inflammation women New Engl J Med : — Register for an event. Accepted : 19 March Rodents and humans that lack either leptin or the leptin receptor LEPR are not only extremely obese, but are also hyperglycemic and extremely insulin resistant
	Show results from All journals This journal. Number of MS components in all women. The risk of CVD in the metabolic syndrome has been considered to result from the presence of multiple CVD risk factors such as dyslipidemia hypertriglyceridemia, an excess of small, dense LDL particles and reduced HDL-cholesterol levels , hypertension, dysglycemia, and a thrombogenic profile that have been reviewed elsewhere — Article CAS PubMed Google Scholar Maresca G, Di Blasio A, Marchioli R, Di Minno G. In clinical practice, waist circumference as central obesity was used and correlated waist circumference with metabolic syndrome.
REVIEW article	DeFronzo RA, Immune support pills E. It is secreted by adipocytes innflammation the development of obesity and distributon to infiltration of monocytes, which differentiate to become Fat distribution and inflammation tissue macrophages. The mechanism for such anx in Korean red ginseng extract sensitivity in the face of jnflammation gain appears to be through the distribuyion of Fat distribution and inflammation by Fat distribution and inflammationwhich has known insulin-sensitizing properties as described above. In addition to β-cells, adiponectin has also been shown to exhibit strong anti-inflammatory effects on other cell types such as macrophages and fibrogenic cells 99, In addition to WAT depots, brown adipose tissue BAT represents a distinct type of adipose tissue that is characterized by its morphology and function, with concentrated mitochondria giving it a characteristic brown appearance. With a primary function of sequestering lipotoxic lipids and the known potential for chronic inflammation, obese adipose tissue has emerged as a potential player in the regulation of these atherogenic factors.
Introduction	Efforts to enhance BAT activation in humans consist of intermittent regular cold exposure, introduction of β 3 -adrenergic receptor agonists, and exercise 29 , However, robust reductions in body weight in humans have not yet been shown to be clinically significant when BAT is activated , necessitating further mechanistic studies to elucidate whether BAT activation is a viable target for metabolic improvement in humans. Whether BAT undergoes similar immune cell changes as WAT under obesogenic conditions is still not clear. Such BAT inflammation reportedly lowers the thermogenic potential of this tissue , presumably due to increased local insulin resistance , , which could reduce the glucose and fatty acid oxidizing capacity of BAT. Similar to BAT, beige adipocyte quantity and functionality appear to be sensitive to local inflammation. A study in which IkB kinase IKK, an enzyme that is required for NFκB activation and subsequent inflammatory cytokine transcription was inactivated in mice, not only blunted adipose tissue inflammation and body weight gain, but enhanced WAT browning Similarly, inhibiting a major intracellular mediator of toll-like receptor 4 TLR4 signaling, interferon regulatory factor 3 IRF3 , blunted WAT inflammation and augmented WAT browning Thus, accumulating evidence suggests that obesity-associated inflammation hinders the thermogenic and insulin sensitizing effects of both BAT and beige adipocytes. Abundant evidence indicates that adiposity and adipose tissue inflammation are associated with insulin resistance, which refers to a reduced response to binding of insulin to its receptor in peripheral tissues such as adipose tissue and skeletal muscle. This differs from glucose effectiveness, which is uptake of glucose by peripheral tissues in an insulin-independent manner. Insulin inhibits hepatic glucose output and stimulates lipogenesis in the liver, both of which are reduced in the presence of insulin resistance. Such desensitization of insulin signaling pathways also inhibits glucose uptake in peripheral tissues and stimulates lipolysis in adipose tissue. To compensate for reduced insulin sensitivity, insulin secretion is increased in order to maintain euglycemia. If the pancreatic beta cells are unable to secrete sufficient insulin to compensate for the reduced insulin sensitivity termed beta cell dysfunction , hyperglycemia will ensue, leading to glucose intolerance and eventually T2DM While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier. Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in 64 , ]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans. Cross-sectional studies in men of European, Asian Indian, and American descent have shown that total, visceral, and subcutaneous adiposity, BMI, and waist circumference are all negatively associated with insulin sensitivity , As noted earlier, adiposity, especially visceral adiposity, is characterized by adipose tissue inflammation. Several hypotheses have been put forth to account for the relationship between adipose tissue inflammation and insulin resistance. These include production of pro-inflammatory cytokines by adipocytes and adipose tissue macrophages discussed previously in the section on WAT Inflammation , excess FFA, decreased adiponectin, increased resistin and retinol binding protein, ceramide accumulation, and ectopic fat accumulation in liver and skeletal muscle It has been shown that adipose tissue mass correlates with circulating FFA in obese humans, with a tendency for individuals with visceral adiposity to have higher FFA turnover — It has also been reported that individuals with T2DM tend to have elevated FFA levels over non-diabetic controls , an effect found to correlate more strongly with insulin sensitivity rather than obesity Consistent with this, one study reported that FFA levels were lower in MHO subjects than those with MUHO In addition to dysregulated energy metabolism, disruption of the endocrine function of obese adipose tissue has now been shown to contribute to insulin resistance, described in more detail below. Adipocytes in obesity simultaneously secrete lower levels of adiponectin and elevated levels of cytokines and chemokines, such as TNFα, IL-6, MCP-1, and SAA. Not only is there evidence that such inflammatory cytokines contribute directly to insulin resistance in hepatocytes and myocytes , they also directly inhibit adiponectin production from adipocytes There is evidence that hypoadiponectinemia plays a role in obesity-associated T2DM — Subjects with T2DM exhibit reduced circulating adiponectin levels , ; similarly, MHO subjects have higher circulating adiponectin than those with MUHO This may be explained by the nature of adipose tissue expansion in these transgenic mice, which had smaller, less inflamed adipocytes and less liver fat content. As discussed in earlier sections, FGF21 is a hormone produced by the liver as well as adipocytes that exerts insulin-sensitizing effects. However, recent evidence has paradoxically suggested an association between serum FGF21 levels and obesity-associated metabolic syndrome , FGF21 levels have been reported to be 2-fold higher in MUHO when compared to MHO Moreover, subjects with T2DM were reported to have significantly higher plasma levels of FGF21 than insulin-sensitive controls, with FGF21 levels positively correlated with BMI, HOMA-IR, and Matsuda index, suggesting a strong correlation with insulin resistance Plasma FGF21 levels also correlated strongly with visceral, epicardial, hepatic, and skeletal muscle ectopic fat levels, measured using slice multidetector CT scanning This conclusion was reached based on some observations that circulating FGF21 levels are increased in obesity, with lower FGF21 receptor expression levels on target tissues such as adipose tissue , However, this notion has been challenged by evidence that obese subjects are equally responsive to pharmacological administration of FGF21 , Thus, it has now been proposed that obesity-associated FGF21 is increased as a compensatory mechanism to preserve insulin sensitivity As such, a clear role for adipocyte-derived FGF21 in obesity and associated metabolic syndrome is still lacking. Evidence suggests that ineffective adipose expansion promotes local inflammation and an insulin resistant phenotype However, sufficient adipogenesis and hyperplasia i. Thus, strategies to increase the recruitment of adipocyte progenitor cells to expand adipose tissue by increasing adipose cell numbers could be protective against the metabolic consequences of obesity. A key structural and functional component of adipose tissue is made up of extracellular matrix ECM molecules, including collagen and proteoglycans such as versican and biglycan, among others Adipose tissue makes large quantities of ECM during active remodeling, as would occur during WAT expansion in obesity — To date, most studies of WAT ECM function have centered around collagen, which can form a scaffold that constrains adipocyte expansion due to mechanical stress , , Targeting ECM components to release adipocytes from such constraints due to excessive ECM production could potentially alleviate the ectopic accumulation of fat that drives the metabolic syndrome. While the majority of adipose tissue in humans is localized subcutaneously , the volume of visceral adipose tissue is believed to be a strong predictor of insulin resistance , independent from subcutaneous fat quantity , The association between insulin resistance and visceral adipose mass is particularly striking in certain ethnic populations, with T2DM rates of While visceral adiposity is positively associated with insulin resistance, there is evidence to suggest that it may not be a causal factor. Other conditions associated with visceral adiposity, such as hepatic fat content, may instead drive insulin resistance , Some clinical studies have dissociated the glucose metabolic effects of visceral adiposity from hepatic lipid accumulation. In one such study, significant differences in insulin sensitivity in the liver, skeletal muscle, and adipose tissue were reported in obese human subjects who differed in hepatic lipid content, with no such differences observed in obese subjects who differed in visceral adiposity Similarly, in a study in which obese subjects were matched for liver fat content, no differences in indices of glucose metabolism were noted Insulin-sensitive MHO individuals tend to have lower visceral and intrahepatic fat accumulation than their MUHO counterparts , , , providing further evidence that these fat depots contribute to insulin resistance. Collectively, while visceral adiposity and hepatic fat content are both strongly associated with whole-body and tissue-specific insulin resistance, hepatic lipid accumulation may play a more direct role in negatively modulating glucose homeostasis. Many studies have suggested that fat distribution is strongly associated with insulin resistance, with visceral adiposity being the strongest predictor of insulin resistance , , While the detrimental effects of visceral and hepatic lipid accumulation on glucose metabolism are clear, it is also becoming increasingly appreciated that lower body subcutaneous adiposity may be metabolically protective — Large-volume liposuction of subcutaneous WAT has shown little to no metabolic benefit in human trials Gluteofemoral adipose mass is positively associated with insulin sensitivity in humans, coupled with a slower rate of lipolysis and subsequent FFA release, lower levels of inflammatory cells and cytokines, and elevated adipokines such as leptin and adiponectin Evidence from animal models has suggested that transplantation of subcutaneous WAT into the visceral cavity of recipient mice promotes less body weight and adiposity gain than transplantation with visceral WAT, resulting in greater insulin sensitivity in the liver and endogenous WAT Taken together, a growing body of evidence suggests that adipose tissue and ectopic lipid distribution contribute to whole-body glucose homeostasis. With the purported potential to improve glucose homeostasis, interest in BAT and beige adipose tissue as therapeutic targets has increased in recent years. Studies in rodents in which BAT is transplanted into diseased mouse models have shown that transplanted BAT improves insulin sensitivity, glucose metabolism, and obesity — , likely mediated by batokine effects. As a highly metabolically active organ, BAT contributes to glucose clearance by taking up relatively large amounts of glucose from the circulation, thus reducing insulin secretion by pancreatic β-cells Indeed, individuals that possess detectable BAT have lower fasting glucose concentrations than those without active BAT Glucose disposal through activated BAT occurs by both insulin-dependent and insulin-independent mechanisms For example, the cold exposure-mediated influx of glucose into active BAT has been suggested to be an insulin-independent process — However, as the insulin receptor is highly expressed in BAT tissue, it is considered to be one of the most sensitive insulin target tissues and thus an important organ for glucose disposal BAT activation further enhances insulin signaling in BAT itself by augmenting insulin-independent glucose uptake associated with thermogenesis and glucose uptake due to insulin signaling. Thus, strategies that activate BAT and beige adipose tissue have the capacity to improve insulin resistance by clearing excess glucose — Several pathologic conditions, including hypercholesterolemia and systemic inflammation, are hypothesized to drive atherosclerotic CVD. With a primary function of sequestering lipotoxic lipids and the known potential for chronic inflammation, obese adipose tissue has emerged as a potential player in the regulation of these atherogenic factors. Obesity has been officially classified as an independent risk factor for CVD by the American Heart Association since , meaning that obesity treatment is likely to lower the incidence of CVD As alluded to in previous sections, people with MHO are at a lower risk of experiencing cardiovascular events than people with MUHO , yet those without obesity are at a considerably lower risk for future events. Thus, even a moderate level of weight loss, if sustainable, could potentially lower the risk of adverse CVD events Possible reasons include confounding factors such as smoking and the presence of co-morbidities that are associated with lower body weights, or the use of BMI rather than measures of visceral obesity for most studies on the obesity paradox. Despite the obesity paradox in those with established CVD, the following sections will provide information regarding potential links between obesity T2DM and CVD. The various features of adipose tissue depots, including ectopic fat, and how they contribute to T2DM and CVD are summarized in Figure 2. Notably, there are many similarities between adipose depot characteristics that contribute to both T2DM and CVD. Figure 2. Adipose depots and ectopic fat sites and their features that contribute to type 2 diabetes mellitus T2DM or cardiovascular disease CVD. Features of intra-abdominal white adipose tissue WAT , subcutaneous fat, hepatic fat, heart and arterial fat inclusive of epicardial, pericardial, and perivascular fat , pancreatic fat, skeletal muscle fat, brown adipose tissue, and a dysbiotic gut that contribute to either T2DM or CVD. Arrows indicate changes in comparison with subjects without T2DM or CVD. The accumulation of visceral fat in obesity is associated with the metabolic syndrome, its associated CVD risk factors, and an increased risk for clinical CVD This distribution of WAT has been shown to have the greatest effect on CVD risk and mortality among patients with normal body weight The risk of CVD in the metabolic syndrome has been considered to result from the presence of multiple CVD risk factors such as dyslipidemia hypertriglyceridemia, an excess of small, dense LDL particles and reduced HDL-cholesterol levels , hypertension, dysglycemia, and a thrombogenic profile that have been reviewed elsewhere — However, there are several additional potential mechanisms by which visceral WAT might contribute directly to CVD that involve FFA, insulin resistance, and inflammation. Visceral WAT has higher lipolytic activity than subcutaneous WAT due to its having fewer insulin receptors, and thus is a significant source of FFA. Visceral-derived FFA can directly impact the liver via the portal vein, facilitating FFA uptake by the liver and subsequent hepatic insulin resistance. Similarly, excess FFA from visceral fat might directly impair lipid metabolism and lead to dyslipidemia, which increases CVD risk. In obese diabetic subjects, plasma FFA levels have been shown to be elevated compared to BMI-matched non-diabetic subjects , supporting the notion that insulin resistance further elevates circulating FFA levels. Moreover, the incidence of T2DM is nearly doubled in patients with the highest levels of FFA 90th percentile when compared with subjects with the lowest FFA levels 10th percentile In one study, obese T2DM subjects who had undergone overnight fasting during pharmacological inhibition of lipolysis exhibited improved insulin sensitivity and glucose tolerance , providing further evidence for an inhibitory effect of FFA on insulin sensitivity. The adipokine profile of visceral WAT also contributes substantially to its association with CVD risk. Obese visceral WAT primarily secretes inflammatory cytokines such as resistin, TNFα, IL-6, IL-1β, MCP-1, and SAA, with reduced levels of adiponectin Plasma adiponectin levels are decreased in patients with CVD Adiponectin is believed to contribute to CVD protection by several mechanisms, including the reduction of lipid levels, repressing expression of inflammatory mediators such as VCAM, ICAM, E-selectin, TNFα, and IL-6, and by acting directly on the heart to improve ischemic injury by activating AMPK and subsequently increasing energy supply to the heart — Adiponectin also stimulates endothelial nitric oxide synthase eNOS , which maintains healthy vascular tone , Thereby, adiponectin would play a protective role in the development of CVD. Conversely, leptin levels are positively associated with acute myocardial infarction, stroke, coronary heart disease, chronic heart failure, and left cardiac hypertrophy — , although the reasons for this remain largely unknown. Leptin receptors are expressed in the heart, indicative of an important impact of direct leptin signaling Resistin is positively associated with systemic inflammatory markers , upregulates endothelial expression levels of VCAM-1 and endothelin-1 and promotes the proliferation of smooth muscle cells Resistin also associates positively with coronary artery calcification levels, and negatively with HDL cholesterol Thus, adipose-derived resistin levels could be used to predict the severity of coronary atherosclerosis Similarly, cytokines and chemokines such as those secreted from obese visceral WAT can induce expression of endothelial adhesion molecules , recruit macrophages , increase thrombosis , and reduce vasoreactivity , and are positively associated with cardiovascular events , While visceral WAT-derived cytokines are associated with these CVD-inducing processes, it is important to note that the direct contribution from visceral WAT is not currently known, as these are also secreted from other tissues. As discussed in previous sections, in addition to cytokines and exclusive adipokines, WAT is also a source of FGF While the liver is considered to be the major source, adipocytes have also been shown to produce FGF21 to varying degrees in response to various stimuli. In addition to its associations with obesity and T2DM, FGF21 levels have also been associated with increased risk for CVD — Subjects with CVD that also had diabetes exhibited even higher levels of FGF21 , suggesting an important role in diabetes-accelerated atherosclerosis. In particular, FGF21 levels have been shown to positively correlate with hypertension and triglyceride levels, and to negatively correlate with HDL-cholesterol levels One study by Lee et al. suggested that plasma FGF21 levels are associated pericardial fat accumulation , which suggests that ectopic fat could be a source of FGF21 in metabolic disease. Further studies are needed to discern whether adipocyte- or hepatic-derived FGF21 contribute to these effects. In stark contrast to these effects of physiological FGF21, pharmacological administration of FGF21 in humans and non-human primates reduces blood glucose, insulin, triglycerides, and LDL cholesterol, and increases HDL cholesterol , , Thus, there is a disconnect between the physiological and pharmacological effects of FGF21 that requires further study. It is becoming increasingly clear that adipose tissue expansion contributes directly to obesity-associated cardiovascular disease risk Obesity is accompanied by not only excess visceral adiposity, but also by excess epicardial and perivascular WAT Due to their proximity to the heart, coronary arteries, and other major arterial blood vessels that are prone to atherosclerosis, it is not surprising that epiWAT and PVAT are important regulators of cardiac and vascular. The respective sizes of these adipose depots are associated with risk factors for the metabolic syndrome, including elevated visceral fat content, blood glucose, hypertension, systemic inflammation, insulin resistance, circulating LDL levels, mean arterial pressure, and atherosclerosis 19 , — , as well as adverse cardiovascular events — The mechanisms behind these associations include increased secretion of pro-inflammatory cytokines, vasoactive factors, and vascular growth factors — ; increased release of lipotoxic FFA , ; increased macrophage content ; increased oxidative stress ; and decreased secretion of adiponectin , which are triggered by obesity. In a prospective cohort of patients with aortic stenosis, a positive association between epiWAT volume and left ventricular mass was found , suggesting that in addition to changes in adipokine secretion, epiWAT could negatively influence cardiac function by placing a restrictive burden on the heart. Mechanisms by which PVAT influences CVD are more nuanced and complex. As an adipose depot that features some characteristics of both WAT and BAT, and with different functions depending on the anatomical location i. abdominal aortic PVAT , PVAT can play either a cardioprotective or a pathological role As obesity progresses, PVAT can become dysfunctional in that it more resembles WAT, and contributes to a pro-inflammatory and lipotoxic microenvironment that promotes atherosclerosis Thus, while PVAT and BAT play atheroprotective roles in healthy individuals, obesity promotes dysfunction of these depots, blunting this protective effect against CVD. Strategies for weight loss are multi-faceted, including combinations of diet and lifestyle modifications, pharmaceutical therapy, and various forms of bariatric surgery While there is some debate over this, it is generally believed that small degrees of weight loss in MUHO obese populations can have a dramatic impact on cardiometabolic health , ; thus, strategies that improve obesity are likely to also decrease risk factors for CVD. Similarly, CVD treatment strategies are centered around a combination of pharmaceutical use and lifestyle modifications, which also impact adipose tissue. In this section, we will describe the effects that various CVD treatment strategies have on adipose tissue metabolism and inflammation. How these treatment strategies impact the contributions of particular adipose depot features to T2DM and CVD are listed in Figure 2. Traditional methods prescribed for weight loss include restricting food intake and increasing energy expenditure. Despite a large number of fad diets that dictate particular proportions of dietary fat, protein, and carbohydrates to facilitate weight loss [summarized in , ], the simple fact remains that for weight loss to occur, energy balance must be negative. Thus, energy intake must be less than energy expended, which includes resting energy expenditure, physical activity, and the thermic effect of food. Subsequently, additional studies have shown that modest weight loss due to dietary changes in people with overweight or obesity is due to roughly equivalent fat lost from subcutaneous and visceral depots, while the addition of exercise leads to more weight loss from subcutaneous fat as well as loss of ectopic skeletal muscle fat — The loss of visceral fat is associated with reduced CVD risk factors, including reduced systemic inflammation, total cholesterol, LDL cholesterol, and triglycerides , , as well as reduced fasting glucose and insulin levels , As the subjects recruited for the Look AHEAD trial had T2DM, this and other post-hoc analyses suggest that weight loss in T2DM subjects also lowers the risk of CVD events , It is well established that aerobic exercise increases fuel mobilization from adipose tissue by increasing lipolysis and subsequent FFA mobilization, which ultimately decreases adiposity and adipocyte size — Such enhanced fuel mobilization is thought to be highest for visceral WAT Hepatic fat is also mobilized and decreased following intense aerobic exercise Studies in mice suggest that not only visceral fat mass is lost with regular exercise, but subcutaneous and brown fat mass are also diminished As expected with fat loss, exercise is coincident with reduced plasma and adipose tissue leptin levels — The effects of exercise-induced fat loss on adiponectin levels are less clear, with some studies showing no changes in circulating adiponectin levels — , some showing increased plasma adiponectin — , and others showing increased subcutaneous WAT expression of adiponectin mRNA — A meta-analysis showed that pediatric subjects with obesity exhibit reduced resistin levels following aerobic exercise Little is known about the impact of exercise on FGF21 in obese humans, but one study suggested that aerobic exercise training in obese women reduced circulating FGF21 levels By contrast, studies in rodents have shown that circulating FGF21 levels are not altered by exercise in obese animals Collectively, such exercise-induced changes to WAT distribution and adipokine secretion likely facilitate the observed improvements in insulin sensitivity and CVD risk factors observed with exercise. While many studies have reported that exercise training increases subcutaneous WAT browning in rodent models of obesity — , there is limited data to support this in humans. Many studies have shown that there is no effect of aerobic exercise training to recruit beige adipocytes in humans However, one study compared subcutaneous WAT from lean, sedentary young men with age- and weight-matched endurance-trained men and reported no differences in beige markers such as UCP1, PGC1A , or CIDEA Another study found evidence of subcutaneous WAT browning i. There is some debate about what role brown or beige adipose tissue would play in exercise, if it indeed occurs. Exercise is known to activate the sympathetic nervous system, which also activates BAT to quickly release stored energy, so it is possible that BAT activation is secondary to exercise-induced sympathetic activation Loss of adipose tissue mediated by dietary changes, exercise, liposuction, or bariatric surgery discussed in the section on Bariatric Surgery is accompanied by decreased markers of adipose tissue and systemic inflammation , Fat loss by liposuction yielded similar changes in systemic inflammatory markers in one study , but did not improve plasma cytokine levels in another The removal of visceral fat from Zucker diabetic fatty rats resulted in dramatic reductions in systemic cytokines ; this suggests that removing visceral fat, rather than the subcutaneous fat that is routinely removed during liposuction, is more advantageous in terms of resolving inflammation. Many studies also have shown that weight loss following bariatric surgery leads to reductions in systemic inflammatory markers , with notable reductions in adipose tissue inflammatory cytokine and macrophage expression — However, some similar studies do not show improvements in adipose tissue inflammation following various weight loss modalities, such as bariatric surgery or very low-calorie diets — It has been suggested that pronounced weight loss over time can lead to improvements in adipose tissue inflammation that were not observed in the same subjects following acute moderate weight loss This implies that adipose tissue inflammation during the initial stages of weight loss could be required for the pronounced adipose tissue remodeling required for fat loss , Metformin is the most commonly prescribed medication to treat T2DM, particularly in subjects with obesity Metformin has been proposed to lower blood glucose levels through suppression of gluconeogenesis in the liver, activation of AMP-activated protein kinase AMPK , inhibition of the mitochondrial respiratory chain complex 1 , and by unknown mechanisms in the gut , Thus, the precise mechanisms by which metformin lower blood glucose are complex and still evolving. While some diabetes medications have adverse effects on body weight, patients taking metformin often lose a small amount of weight [reviewed in ]. Studies in T2DM suggest that metformin may reduce body fat stores and promote a more metabolically healthy fat distribution — The effect of metformin on adiposity may be partially due to reported nausea and anorexic effects of the drug — With much recent attention focused on BAT as a potential target for obesity treatment, it has recently been shown that BAT is an important effector organ in the glucose-lowering effects of metformin Some studies have reported increases in omentin following metformin therapy, which could be due to visceral fat loss Metformin also reduces hepatic steatosis through inhibition of ApoA5 and steroyl-CoA desaturase-1 SCD1 which combine to limit de novo lipid synthesis, which is partially mediated by its actions on AMPK and liver X receptor LXR activity , It also has been suggested that metformin reduces ECM remodeling that is dysregulated in obesity see previous section on adipose tissue plasticity , and reduces lipogenesis In addition to the increasingly recognized anti-obesity effects of metformin, its ability to improve CVD risk is also becoming apparent The mechanism may include improvements in the lipid profile, such as mild reductions in plasma VLDL cholesterol and triglycerides with slight elevations in HDL cholesterol In addition, metformin has been shown to have anti-inflammatory properties, reported to reduce circulating CRP and MCP-1, reduce NFκB activity, and to reduce advanced glycation end products AGE — Glucagon-like peptide-1 GLP-1 is a peptide hormone that is continuously secreted at low levels during fasting by intestinal L cells. Consumption of a meal enhances GLP-1 secretion, which functions to reduce plasma glucose levels by stimulating insulin secretion from pancreatic beta cells. In addition, GLP-1 receptors are abundant in brain areas that control food intake regulation, such as the hypothalamus, where GLP-1 functions to reduce the drive to eat , Thus, several GLP-1 receptor agonists have been developed to mimic the glucose-lowering and anorexic effects of GLP-1 to treat obesity and T2DM. Liraglutide, a GLP-1 receptor agonist, has shown efficacy in not only glucose control, but also in promoting weight loss and reduced waist circumference based on results from the Liraglutide Effect and Action in Diabetes LEAD study — Liraglutide has also been shown to reduce total adiposity, and specifically visceral fat mass , While initially described as being devoid of GLP-1 receptors , it has now been confirmed that adipocytes express the GLP-1 receptor , Adipose tissue may therefore be an additional target for GLP-1 receptor agonists to promote adipose remodeling by unknown mechanisms. In addition to its effects on body weight and glucose metabolism, GLP-1 receptor agonists may also provide protection against CVD The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results LEADER trial showed that liraglutide lowered the risk of myocardial infarction and non-fatal stroke among patients with T2DM that had high CVD risk GLP-1 receptor agonist treatment has been shown to protect against atherosclerosis in animal models and in humans, potentially by lowering plasma lipids and by reducing circulating CRP and soluble ICAM-1 levels — Liraglutide, when administered in combination with metformin as indicated for the treatment of T2DM, has been shown to reduce epicardial WAT volume with simultaneous increased omentin expression Thus, liraglutide may provide cardioprotection through reduced levels of ectopic fat, lipids, and inflammation. Inhibitors of the sodium-glucose cotransporter 2 SGLT-2 have been shown to reduce blood glucose levels in subjects with T2DM by enhancing urinary glucose excretion The SGLT-2 inhibitor empagliflozin, alone and in combination with the GLP-1 receptor agonist liraglutide, has been shown to reduce CVD risk , as well as cardiovascular death to a greater extent than statins alone Empagliflozin also is associated with decreased hypertension, reduced arterial stiffness, and decreased vascular resistance , In both rodents and humans with non-alcoholic fatty liver disease, SGLT-2 inhibitors have been shown to reduce ectopic liver fat by blunting de novo hepatic lipogenesis — , with reduced alanine transaminase ALT and aspartate transaminase AST levels , two markers of hepatic metabolic stress. Furthermore, empagliflozin is associated with weight loss in humans when administered in combination with other therapeutics, such as metformin, thiazolidinediones, and sulfonylureas — In rodents, SGLT-2 inhibitors have been shown to suppress high fat diet-induced weight gain and to markedly reduce obesity-induced inflammation in WAT, potentially by increasing fat oxidation and the recruitment of beige adipose tissue , Thus, in addition to correcting hyperglycemia, SGLT-2 inhibitors can also impact adipose tissue physiology; whether this is through direct or indirect mechanisms remains to be elucidated. Bariatric surgical techniques, including Roux-en-Y gastric bypass RYGB and sleeve gastrectomy, are widely acknowledged to be the most effective treatment strategies for obesity, achieving relatively low levels of obesity remission Within the first year of surgery, some patients experience the loss of around half of their adipose tissue mass , often with roughly equivalent losses from subcutaneous and visceral WAT , As weight loss progresses, studies have shown that later weight loss is largely from visceral depots — , an effect that correlates with the degree of diabetes remission It has also been reported that ectopic skeletal muscle and pancreatic fat are reduced following bariatric surgery , , , which could contribute to improved glucose metabolism. Studies in humans have reported that subcutaneous adipocytes become smaller following bariatric surgery, resembling adipocytes from lean individuals, but that total adipocyte number remains unchanged , Little is known regarding the size and number of visceral adipocytes, which are extremely difficult to sample from humans. As expected with reduced adipocyte size, leptin levels have been shown to decrease following bariatric surgery, while adiponectin has been shown to increase in some studies , , but not in others , Whether changes in adipokine secretion are important for the sustained metabolic improvements following bariatric surgery or whether they simply reflect the adipose remodeling remain to be elucidated. However, it is worth noting that one study has shown that adiponectin levels are elevated only 2 weeks following bariatric surgery, before significant weight loss has occurred, suggesting that adipokine responses may be independent from weight loss Following bariatric surgery, obesity-associated systemic inflammation persists for as much as 1 month, as indicated by IL-6 and CRP levels , , Some of this inflammation has been attributed to the surgery itself However, by 6 to 12 months post-surgery, circulating IL-6, CRP, and MCP-1 are typically reduced below pre-surgery levels , , — , an effect that may be due to fat loss. Importantly, it is not yet clear what effect weight loss due to bariatric surgery has specifically on adipose tissue inflammation. With insulin sensitivity being substantially improved in all of these studies, these latter studies present a potential disconnect between adipose tissue inflammation and insulin sensitivity that requires further study. However, it must be noted that the adipose tissue sampled in these studies was from subcutaneous depots, due to ease of sampling. Given that visceral WAT is more prone to inflammatory changes, it is possible that visceral WAT inflammation is more impacted by bariatric surgery than subcutaneous WAT. Bariatric surgery has been shown to upregulate FGF21 in humans, an effect that appears to be specific to RYGB-induced weight loss, as this effect is not observed following weight loss due to caloric restriction or sleeve gastrectomy — Importantly, it is not known if such FGF21 derives from the liver or adipose tissue. One study has shown that increased FGF21 is associated with improved HOMA-IR in RYGB subjects, an effect that remains when adjusted for adiposity , introducing the possibility that elevated FGF21 levels serve to impact glucose homeostasis. Given that FGF21 has been shown to be elevated in obesity, and in particular in subjects with insulin resistance , the notion that FGF21 levels would become even further elevated following RYGB surgery, a procedure which rapidly improves insulin sensitivity, represents a paradox. Various forms of bariatric surgery have been shown to evoke long-term benefits including sustained and considerable weight loss as well as rapid and sustained remission of T2DM and reduced risk of CVD-related mortality Bariatric surgery also is associated with improved hypertension, but not a reduced risk of incident hypertension Interestingly, the CRP reduction observed following bariatric surgery was most pronounced in subjects that regained the most insulin sensitivity , suggesting an important link between improved glucose metabolism and CVD. TZDs are synthetic peroxisome proliferator-activated receptor gamma PPARγ activators that have been used to treat T2DM for decades — The mechanism for such improvements in insulin sensitivity in the face of weight gain appears to be through the induction of adiponectin by TZDs , which has known insulin-sensitizing properties as described above. Activation of PPARγ by TZDs not only enhances adipogenesis, it also alleviates inflammatory cytokine secretion associated with obesity and reduces ectopic fat deposition in tissues such as the liver and skeletal muscle There appears to be a reciprocal relationship between inflammatory cytokines and adiponectin. For example, in vitro experiments in cultured adipocytes revealed that treatment with adiponectin reduces cytokine secretion , , while treatment with cytokines drastically reduces adiponectin expression and secretion , , Due to greater adipose lipid storage potential, TZDs should therefore reduce plasma triglyceride levels, which appears to be the case for pioglitazone but not rosiglitazone — This may in part account for the beneficial cardiovascular effects of pioglitazone in a clinical trial Characteristic features of MUHO and the metabolic syndrome include adipose tissue and systemic inflammation, which may play a role in the pathogenesis of atherosclerotic CVD. Therefore, an approach that inhibits inflammation would seem logical. The CANTOS trial, in which CVD events were reduced using an IL-1β antagonist, canakinumab , was the first successful proof of concept study using an anti-inflammatory approach for the prevention of recurrent CVD events. A more recent study showed that colchicine, an old drug that has powerful anti-inflammatory properties, reduced recurrent ischemic events when administered after a myocardial infarction Statins, which inhibit 3-hydroxymethyl-glutaryl-coenzyme A reductase HMG-CoA reductase to reduce LDL cholesterol levels, also have anti-inflammatory properties — Whether this anti-inflammatory effect of statins plays a role in the well-documented effect of statins in inhibiting clinical CVD events and CVD mortality , is unknown. Even less is known about the effect of statins on inhibiting inflammation in adipose tissue, although statins have been shown to reduce epicardial fat accumulation A clue to the potential role of statins in adipose tissue inflammation is provided by the recent demonstration that myeloid-specific deletion of HMG-CoA reductase improved glucose tolerance in obesity induced by a high fat diet, as a result of decreased macrophage recruitment into adipose tissue These changes occurred independently of weight loss and provide impetus for further studies on the effect of statins on adipose tissue inflammation. Regardless, the effect of statins on adipose tissue inflammation is an area that warrants further investigation. The trillions of bacteria that reside within our digestive tract, termed gut microbiota, play an important symbiotic role in shaping our metabolic health. The specific bacterial populations that inhabit our gut can have substantial metabolic impact in relation to obesity, as it is becoming increasingly recognized that that the gut microbiota may contribute to the pathology of obesity — Dysbiosis, or microbial imbalance in the body, has been associated with obesity in both humans and mice, and can be reversed with weight loss — It is known that gut bacteria can influence distinct host organ systems indirectly and specifically through the release of particular microbial metabolites such as bile acids, short-chain fatty acids SCFA , and others. Adipose tissue is a notable target of these microbial metabolites As such, treatments that target the microbiome and modulate microbial metabolism could improve metabolic health. There is growing evidence that gut dysbiosis can contribute directly to atherosclerotic CVD — , These processes are described below. Increased intestinal permeability allows inflammatory bacterial components to enter the systemic circulation to trigger an inflammatory response in diverse tissues such as the liver and adipose tissue. Obese mice and humans have been shown to exhibit gut dysbiosis , with increased proportions of endotoxin-producing gut bacteria and elevated circulating levels of lipopolysacharide that correlate with metabolic disease state such as obesity or T2DM , Such metabolic endotoxemia is reduced following antibiotic treatment or RYGB surgery-induced weight loss Thus, a compromised intestinal barrier may contribute to systemic inflammation that is characteristic of obesity and CVD Gut dysbiosis contributes to dysregulated bile acid metabolism , leading to hyperlipidemia and hyperglycemia , Bile acids produced by the liver facilitate the absorption of dietary fat in the small intestine, and are known to regulate lipid and glucose metabolism through the FXR , FXR activation by bile acids initiates a negative feedback pathway, such that bile acid synthesis is inhibited when FXR is activated. Secondary bile acids have been shown to exert an anti-inflammatory phenotype in macrophages and hepatocytes — Bariatric surgery increases plasma bile acid concentrations before any significant weight loss has been achieved — Metabolic benefits from bariatric surgery, including weight loss and improved glucose metabolism, were absent in mice lacking the TGR5 receptor , suggesting an important role for bile acids in the metabolic improvements associated with bariatric surgery. Indeed, adipocyte TGR5 is required for adipogenesis and a metabolically healthy adipokine profile, including secretion of adiponectin and repression of inflammatory cytokines , Similarly, deficiency of FXR promotes adipocyte dysfunction, exemplified by impaired adipogenesis, defective insulin signaling, and reduced lipid storage capacity Collectively, these previous studies suggest that intact bile acid signaling is required for adipocyte homeostasis. Thus, equilibrium between dietary-intestinal- and microbiome-intestinal-derived bile acids is important for metabolic health associated with lipid metabolism. The gut microbiota composition and metabolism are therefore important contributors to metabolic health. SCFA, including predominantly acetate, propionate, and butyrate, are produced in the gut to varying degrees, depending on the fermentable carbohydrate-based substrates available i. SCFA serve as signaling molecules to remote organ systems, with impacts on autonomic regulation of systemic blood pressure, systemic inflammation, and other cellular functions. Dysbiotic gut bacteria that is observed in metabolic pathologies such as obesity and T2DM has been characterized by taxonomic shifts that produce fewer SCFA, with notably less butrate produced in the gut — Evidence from pre-clinical models suggests that SCFA administration could improve metabolic disease states such as obesity, T2DM, and atherosclerosis — Adipocytes express high levels of key receptors for SCFA, including GPR43 Genetic deletion of GPR43 from adipocytes results in spontaneous obesity, while overexpression of adipocyte GPR43 protects mice from obesity As such, adipose homeostasis can be directly modulated by the gut microbial composition and subsequent SCFA profile. Health benefits of giving SCFA to obese rodents include weight loss , improved glucose metabolism, reduced inflammation — , and reduced LDL-cholesterol , , among others. The gut microbiota are now considered to be a distinct organ system with endocrine properties that can directly and profoundly modulate the host immune system , When gut bacteria become dysbiotic, resulting immune deficiencies may contribute to the pathogenesis of obesity, T2DM, and CVD The precise mechanisms by which gut microbiota modulate host immunity [reviewed in ] are beyond the scope of this review. However, some mechanisms by which microbial-derived metabolites can modulate adipose tissue function will be described herein. SCFA such as butyrate have been shown to dampen subcutaneous and visceral WAT inflammation by inhibiting NFκB activation , Similarly, secondary bile acids negatively correlate with inflammatory pathways in WAT, suggesting an anti-inflammatory effect Bacterial endotoxin, circulating levels of which increase during metabolic diseases that exhibit metabolic endotoxemia, readily promotes adipose tissue inflammation by activating toll-like receptor 4 TLR4 , which is highly expressed in adipocytes as well as macrophages Thus, various metabolites produced by the gut microbiota are known to modulate adipose tissue inflammation directly through the circulation. Probiotics are commercial preparations of live bacteria designed to be ingested, with the intention of colonizing the gut with the ingested bacteria, or at a minimum to confer a health benefit to the host. Prebiotics, on the other hand, are non-digestible dietary substrates designed to promote an abundance of gut-healthy bacteria, with inferred benefit to the host Synbiotics are preparations that combine particular pre- and pro-biotics, as it is becoming clear that defined fiber substrates increase probiotic colonization efficiency. Pre- and pro-biotics and synbiotics are relatively inexpensive alternatives to conventional CVD medications, with fewer side effects Mechanisms by which pre- and pro-biotic-mediated changes in the gut microbiota may improve adipose function are still emerging, but may include the promotion of an anti-inflammatory milieu including reducing intestinal permeability to decrease circulating endotoxins , enhancing fat oxidation, recruitment of beige adipocytes, increased energy expenditure, and improved lipoprotein profile, which collectively could improve insulin sensitivity and reduce ectopic fat to combat T2DM and CVD — While it is generally accepted that particular pre- and pro-biotics reduce diet-induced weight and adiposity gain in animal models , — , human intervention studies to date showing efficacy of probiotic treatment are still emerging , , warranting further study Obesity results in many changes to adipose tissue, including adipocyte hypertrophy and hyperplasia, infiltration of inflammatory cells, changes in the ECM, and altered adipokine secretion patterns. A critical determinant of whether obesity is likely to lead to metabolic complications such as insulin resistance, the metabolic syndrome, T2DM and CVD is the site where adiposity increases, particularly intra-abdominal, epicardial and perivascular depots, as well as other ectopic sites such as liver, skeletal muscle and pancreas. Ectopic fat accumulation at these sites demonstrate different metabolic, adipokine, and inflammatory profiles from excess white adipose tissue that accumulates subcutaneously, which is predominantly in a lower body distribution and contributes to a less unhealthy form of obesity. Several mechanisms by which these metabolic and inflammatory changes to different adipose tissue depots could influence the metabolic syndrome and its downstream consequences are potential targets for intervention. LH and AC reviewed the literature and contributed to the preparation of this manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among us adults, doi: PubMed Abstract CrossRef Full Text Google Scholar. Abdullah A, Peeters A, de Courten M, Stoelwinder J. The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies. Diabetes Res Clin Pract. Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, Int J Obes Relat Metab Disord. Centers for Disease Control and Prevention CDC. Prevalence of overweight and obesity among adults with diagnosed diabetes—United States, and MMWR Morb Mortal Wkly Rep. Google Scholar. NCD Risk Factor Collaboration NCD-RisC. Worldwide trends in diabetes since a pooled analysis of population-based studies with 4. CrossRef Full Text Google Scholar. Defronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American heart association's strategic impact goal through and beyond. Cornier MA, Després JP, Davis N, Grossniklaus DA, Klein S, Lamarche B, et al. Assessing adiposity: a scientific statement from the American heart association. Flint AJ, Hu FB, Glynn RJ, Caspard H, Manson JE, Willett WC, et al. Excess weight and the risk of incident coronary heart disease among men and women. Lee CM, Huxley RR, Wildman RP, Woodward M. Indices of abdominal obesity are better discriminators of cardiovascular risk factors than bmi: a meta-analysis. J Clin Epidemiol. Chusyd DE, Wang D, Huffman DM, Nagy TR. Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. The sponsors didn't have any roll in the study design, data collection or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Obesity is a growing problem worldwide, especially in countries where socioeconomic circumstances improve [ 1 ]. In the Netherlands the incidence of overweight and obesity is rising [ 2 ]. Obesity is related to many diseases, including diabetes and cardiovascular disease [ 3 , 4 ], there is also increasing evidence on the association between obesity and tumorigenesis. The underlying mechanisms linking obesity to cancer development are complex and may not be identical in all tumour types [ 5 , 6 ]. There are three main hypotheses linking obesity to the development of cancer. Considering all cancer types, endometrial cancer EC incidence has the strongest positive correlation with BMI [ 7 — 9 ]. In EC, long-term unopposed oestrogen stimulation has been established to play a causative role, especially in the aetiology of the endometroid subtype. Adipose tissue is a very complex endocrine organ that produces adiponectin, leptin, and also steroid hormones. In premenopausal women the ovaries are the main source of oestrogen production [ 10 — 12 ]. However, after menopause, the subcutaneous adipose tissue is the most important producer of oestrogens due to the presence of aromatase, which converts androgens to oestrogens [ 13 ]. This mechanism of the production of endogenous sex-steroids plays an important role in the development of EC. Furthermore, obesity-mediated inflammation and insulin resistance have also shown to be important in this process [ 5 , 6 , 14 ]. Chronic hyperinsulinemia, which is common in obese women, has an effect on cell proliferation directly by high insulin levels and indirectly by higher levels of circulating insulin growth factors IGFs. The chronic inflammation in obese patients results in a higher level of leptin anti-apoptotic and pro-angiogenetic and a lower level of adiponectin which as a result promotes cell proliferation and inhibits cell death. These three mechanisms are thought to play an important role in the development of EC [ 4 , 5 ]. The chronic hyperinsulinemia and systemic inflammation possibly also explains why also for the non-endometrioid subtype, the incidence rate is positively associated with weight gain [ 15 , 16 ]. BMI is a simple, and clinically easily applicable indicator, yet does not cover the complexity of fat distribution in visceral- and subcutaneous compartments, nor the ratio between muscle tissue and fat tissue [ 16 , 18 ]. Internationally the importance of fat distribution is gaining more attention [ 19 — 21 ]. Previous study showed that a higher visceral fat percentage was a negative prognostic biomarker in non-endometrioid EC NEEC [ 19 ] compared to subcutaneous fat which is important for oestrogen production through increased aromatase activity [ 20 , 22 , 23 ]. Fat distribution can be measured by imaging methods like CT and MRI or estimated by measurements of skinfolds, DXA-scan and hip-waist circumference. The latter divides women into two groups, women with an apple figure who presumably have more visceral fat and women with a pear figure who most likely have more subcutaneous fat. The MRI an CT related measurements can distinguish between subcutaneous and visceral adipose tissue [ 5 ]. Adipose tissue compartments, determined by CT segmentation scans, have been correlated to systemic hormone levels, tumour inflammation and pathway activation in a number of studies [ 19 — 22 ]. In the light of the differences between adipose tissue in the various compartments, the relative increase in central obesity visceral obesity through the menopausal transition is of potential additional importance [ 24 ]. Through the rising prevalence of obesity worldwide, it is expected that the EC incidence will continue to rise [ 1 , 15 , 25 , 26 ]. In the more affluent countries, EC is the most frequent gynaecological malignancy [ 27 , 28 ]. The primary treatment of EC consists of hysterectomy with BSO. Removal of ovaries serves three goals: 1, it is part of the staging procedure of EC; 2, to exclude the chance of concurrent ovarian cancer and 3, it leads to reduction of the remaining oestrogen and androgen production and thus possibly reduces risk of recurrence. It is uncertain to what extent the sex steroid hormone and inflammatory levels drop after BSO, especially in obese women with endometrial cancer. Removal of the ovaries demonstrates to what extent oestrogen production is or was driven by the ovaries or the adipose tissue compartment. Pinpointing this more specifically will help in further understanding the role of adipose tissue in the development of EC. This is a prospective observational cohort study. Patients will be recruited from four hospitals including two academic hospitals academic hospital Maastricht AZM and Radboud university medical centre Radboudumc and two large teaching hospitals Canisius Wilhelmina Ziekenhuis CWZ and VieCuri. Inclusions started from 1st of September in AZM and Radboudumc and inclusions at CWZ and VieCuri will start in As of this moment the study is actively recruiting. All participants will provide written informed consent. The aim of this study is to compare hormone levels and inflammatory markers after BSO in obese and non-obese patients. endometrial cancer on changes in hormone levels and inflammatory markers after BSO in obese and non-obese patients, and to compare the effect of BSO on menopausal complaints. We hypothesize that obese post-menopausal women will still have relatively high circulating concentration of oestrogen, especially women with a high subcutaneous fat percentage. Total number of participants is women. Patients will be included pre-operatively. In case of a final diagnosis being ovarian malignancy, this participant will be excluded and a patient with a benign diagnosis included instead. There are no previous studies with comparable analysis, allowing for a formal sample size calculation. Therefore, we have taken the difference in hormone level as the starting point for a sample size calculation. We have chosen to include women, 80 obese and 80 non-obese. Three time points for patients with benign disease T1-T3 and four time points T1-T4 for patients with endometrial cancer EC. At three women with benign diagnoses or four women with EC different time points data will be collected from the subjects. At timepoint 1 T1 , a physical examination is conducted where hip and waist circumference are measured and patient variables including age, height, weight, BMI, history, cumulative illness rating scale CIRS and menopausal status collected. Furthermore, routine abdominal CT imaging will be performed in all patients. Finally, patients are requested to answer a validated questionnaire, the Green climacteric scale enquiring into presence of menopausal symptoms, and are asked to answer three questions on their physical activity level. At timepoint 2 T2 subjects will undergo the clinically indicated surgical procedure. At start of surgery, a fasting blood draw will be obtained to measure oestrogen levels and systemic inflammation markers. During surgery subcutaneous adipose tissue and visceral adipose tissue fat apron and intestinal epiploic fat as well as tumour where applicable will be collected, and snap frozen. At timepoint 3 T3 4 to 6 weeks postoperatively, another fasting blood draw is obtained for measurement of oestrogen levels and systemic inflammation markers. In case of a recent infection the blood draw will be postponed until 10 days after the end of the infection. In case of adjuvant therapy, the postoperative blood draw will be performed latest at start of the adjuvant therapy. Finally, subjects will be asked to fill in the Green climacteric scale questionnaire a second time. For subjects with the diagnosis of EC clinical follow-up data will be collected during 3 years T4. Using the abdominal CT-scans, abdominal fat volumes will be segmented and quantified using a semi-automatic dedicated software iNtuition, TeraRecon Inc. San Mateo, CA, USA [ 20 , 30 ]. The biospecimens will be temporarily stored prior to use in this study at the MUMC Biobank [ 31 ]. In the Biobank Information System BIS type, date and volume of each specimen is recorded. A selection of steroid hormones including oestrogens, androgens, progestogens and corticosteroids as well as local adiponectin, resistin, leptin will be determined in the collected adipose tissue. Inflammatory markers both locally in fat tissue macrophages, T cells: TNF-α, IL-6, and IL-1β and systemically blood including C-reactive protein CRP , interleukin 1 beta IL1β , interleukin 6 IL6 , tumour necrosis factor alpha TNFα , insulin-like growth factor 1 IGF1 , will be determined. Samples will be further characterised by omics technologies genomics, transcriptomics, proteomics and metabolomics. Generated data will be used for biomarker discovery, this data will be used to explore the cellular pathways underlying the various patient characteristics. Pre- and postoperative questionnaires will be analysed and compared. The Green climacteric Scale, assessing menopausal complaints, can be divided into three subcategories; psychological, physical and vasomotor complaints [ 32 ]. We will assess all three subcategories separately to evaluate if there are any differences in the groups of patients pre vs. postmenopausal and obese vs. non-obese patients. Using a population-based inclusion, we would likely have too low numbers in some groups to allow for meaningful analyses. However, as a consequence the external validity is somewhat reduced. Variables will be analysed quantitatively CT derived markers, hormones and inflammatory markers or qualitatively menopausal symptoms and stratified by menopausal status and BMI. Comparison of characteristics and study variables will be performed using Chi squared tests categorical data and Mann Whitney U test or student t-test continuous variables, depending on normality of distribution. Additionally, correlations between inflammatory markers in adipose tissue and circulating oestrogen levels after treatment and outcome are observed. The goal of this prospective cohort study is to explore the differences between obese and non-obese women as well as the importance of fat distribution in relation to EC. This study set up, with two academic hospitals and two big teaching hospitals, is well suited to better understand the relation between obesity and endometrial cancer. Because we will include a big range of women with different BMI, menopausal status and pathology, we think this is the perfect setup to generate those much needed knowledge. A strength of this study is that the big difference in BMI between the two groups will optimally allow for finding any existing obesity-related differences in hormone levels and inflammatory markers. A possible limitation of the resulting BMI gap may thus be the translation of this effect on to the intermediate population. When looking at prevalence of obesity in the Netherlands in , we see that However, data from the Netherlands Comprehensive Cancer Organisation specific for women with endometrium carcinoma shows a mean BMI of m 2 in in this population. Of the EC patients in , Therefore it is most likely that if we find differences in our population, and further research should confirm this also for the intermediate BMI group BMI 25— Because routine CT imaging, due to cost and radiation is not suitable for application in a healthy general population, waist-hip measurement may represent an easy and attractive alternative to CT if this is correlated to the CT morphometric markers. Previous studies have found several clues for a relationship between obesity and endometrial cancer [ 5 — 7 , 14 ]. Finally, our study will be able to relate the occurrence of menopausal complaints to BMI and fat distribution, which has not been previously addressed in in existing literature. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Article Authors Metrics Comments Media Coverage Peer Review Reader Comments Figures. Abstract Background Obesity is a growing problem worldwide, especially in countries with improved socioeconomic circumstances. Objective The aim of this study is to compare hormone levels and inflammatory markers after bilateral salpingo-oophorectomy BSO in obese and non-obese patients. Methods Prospective multicentre observational cohort study. Discussion We hypothesize that BMI, the type of fat distribution, and possibly the underlying pathology significantly influence in hormone levels, and systemic inflammation changes after BSO. Introduction Obesity is a growing problem worldwide, especially in countries where socioeconomic circumstances improve [ 1 ]. Download: PPT.

Fat distribution and inflammation -

Simonsick, Alka M. Kanaya, Marjolein Visser, Denise K. Houston, Barbara J. Nicklas, Frances A. Tylavsky, Suzanne Satterfield, Bret H. Goodpaster, Luigi Ferrucci, Tamara B. The protective mechanisms by which some obese individuals escape the detrimental metabolic consequences of obesity are not understood.

This study examined differences in body fat distribution and adipocytokines in obese older persons with and without metabolic syndrome. Additionally, we examined whether adipocytokines mediate the association between body fat distribution and metabolic syndrome.

Thirty-one percent of these obese men and women did not have metabolic syndrome. Additionally, those with metabolic syndrome had significantly higher levels of interleukin-6 IL-6 , tumor necrosis factor-α TNF-α , and plasminogen activator inhibitor-1 PAI-1 than individuals without metabolic syndrome.

Per standard deviation higher in visceral fat, the likelihood of metabolic syndrome significantly increased in women odds ratio OR : 2. In contrast, the likelihood of metabolic syndrome decreased in both men OR: 0.

These associations were partly mediated by adipocytokines; the association between thigh subcutaneous fat and metabolic syndrome was no longer significant in men. In summary, metabolically healthy obese older persons had a more favorable fat distribution, characterized by lower visceral fat and greater thigh subcutaneous fat and a more favorable inflammatory profile compared to their metabolically unhealthy obese counterparts.

T1 - Body fat distribution and inflammation among obese older adults with and without metabolic syndrome. Thirty-one percent of these obese men and women did not have metabolic syndrome. The search will be preserved in your account and can be re-run at any time.

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Login Login. Body Fat Distribution and Inflammation Among Obese Older Adults With and Without Metabolic Syndrome Koster, Annemarie Stenholm, Sari Alley, Dawn E Kim, Lauren J Simonsick, Eleanor M Kanaya, Alka M Visser, Marjolein Houston, Denise K Nicklas, Barbara J Tylavsky, Frances A Satterfield, Suzanne Goodpaster, Bret H Ferrucci, Luigi Harris, Tamara B Source: Obesity The protective mechanisms by which some obese individuals escape the detrimental metabolic consequences of obesity are not understood.

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What do you think of this resource? Give us your opinion. Confirm Cancel. x Close the export window. Data Availability: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. The sponsors didn't have any roll in the study design, data collection or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist. Obesity is a growing problem worldwide, especially in countries where socioeconomic circumstances improve [ 1 ]. In the Netherlands the incidence of overweight and obesity is rising [ 2 ].

Obesity is related to many diseases, including diabetes and cardiovascular disease [ 3 , 4 ], there is also increasing evidence on the association between obesity and tumorigenesis. The underlying mechanisms linking obesity to cancer development are complex and may not be identical in all tumour types [ 5 , 6 ].

There are three main hypotheses linking obesity to the development of cancer. Considering all cancer types, endometrial cancer EC incidence has the strongest positive correlation with BMI [ 7 — 9 ].

In EC, long-term unopposed oestrogen stimulation has been established to play a causative role, especially in the aetiology of the endometroid subtype.

Adipose tissue is a very complex endocrine organ that produces adiponectin, leptin, and also steroid hormones. In premenopausal women the ovaries are the main source of oestrogen production [ 10 — 12 ]. However, after menopause, the subcutaneous adipose tissue is the most important producer of oestrogens due to the presence of aromatase, which converts androgens to oestrogens [ 13 ].

This mechanism of the production of endogenous sex-steroids plays an important role in the development of EC. Furthermore, obesity-mediated inflammation and insulin resistance have also shown to be important in this process [ 5 , 6 , 14 ].

Chronic hyperinsulinemia, which is common in obese women, has an effect on cell proliferation directly by high insulin levels and indirectly by higher levels of circulating insulin growth factors IGFs. The chronic inflammation in obese patients results in a higher level of leptin anti-apoptotic and pro-angiogenetic and a lower level of adiponectin which as a result promotes cell proliferation and inhibits cell death.

These three mechanisms are thought to play an important role in the development of EC [ 4 , 5 ]. The chronic hyperinsulinemia and systemic inflammation possibly also explains why also for the non-endometrioid subtype, the incidence rate is positively associated with weight gain [ 15 , 16 ].

BMI is a simple, and clinically easily applicable indicator, yet does not cover the complexity of fat distribution in visceral- and subcutaneous compartments, nor the ratio between muscle tissue and fat tissue [ 16 , 18 ]. Internationally the importance of fat distribution is gaining more attention [ 19 — 21 ].

Previous study showed that a higher visceral fat percentage was a negative prognostic biomarker in non-endometrioid EC NEEC [ 19 ] compared to subcutaneous fat which is important for oestrogen production through increased aromatase activity [ 20 , 22 , 23 ].

Fat distribution can be measured by imaging methods like CT and MRI or estimated by measurements of skinfolds, DXA-scan and hip-waist circumference. The latter divides women into two groups, women with an apple figure who presumably have more visceral fat and women with a pear figure who most likely have more subcutaneous fat.

The MRI an CT related measurements can distinguish between subcutaneous and visceral adipose tissue [ 5 ]. Adipose tissue compartments, determined by CT segmentation scans, have been correlated to systemic hormone levels, tumour inflammation and pathway activation in a number of studies [ 19 — 22 ].

In the light of the differences between adipose tissue in the various compartments, the relative increase in central obesity visceral obesity through the menopausal transition is of potential additional importance [ 24 ].

Through the rising prevalence of obesity worldwide, it is expected that the EC incidence will continue to rise [ 1 , 15 , 25 , 26 ]. In the more affluent countries, EC is the most frequent gynaecological malignancy [ 27 , 28 ].

The primary treatment of EC consists of hysterectomy with BSO. Removal of ovaries serves three goals: 1, it is part of the staging procedure of EC; 2, to exclude the chance of concurrent ovarian cancer and 3, it leads to reduction of the remaining oestrogen and androgen production and thus possibly reduces risk of recurrence.

It is uncertain to what extent the sex steroid hormone and inflammatory levels drop after BSO, especially in obese women with endometrial cancer. Removal of the ovaries demonstrates to what extent oestrogen production is or was driven by the ovaries or the adipose tissue compartment.

Pinpointing this more specifically will help in further understanding the role of adipose tissue in the development of EC. This is a prospective observational cohort study.

Patients will be recruited from four hospitals including two academic hospitals academic hospital Maastricht AZM and Radboud university medical centre Radboudumc and two large teaching hospitals Canisius Wilhelmina Ziekenhuis CWZ and VieCuri. Inclusions started from 1st of September in AZM and Radboudumc and inclusions at CWZ and VieCuri will start in As of this moment the study is actively recruiting.

All participants will provide written informed consent. The aim of this study is to compare hormone levels and inflammatory markers after BSO in obese and non-obese patients. endometrial cancer on changes in hormone levels and inflammatory markers after BSO in obese and non-obese patients, and to compare the effect of BSO on menopausal complaints.

We hypothesize that obese post-menopausal women will still have relatively high circulating concentration of oestrogen, especially women with a high subcutaneous fat percentage.

Total number of participants is women. Patients will be included pre-operatively. In case of a final diagnosis being ovarian malignancy, this participant will be excluded and a patient with a benign diagnosis included instead. There are no previous studies with comparable analysis, allowing for a formal sample size calculation.

Therefore, we have taken the difference in hormone level as the starting point for a sample size calculation. We have chosen to include women, 80 obese and 80 non-obese.

Three time points for patients with benign disease T1-T3 and four time points T1-T4 for patients with endometrial cancer EC. At three women with benign diagnoses or four women with EC different time points data will be collected from the subjects.

At timepoint 1 T1 , a physical examination is conducted where hip and waist circumference are measured and patient variables including age, height, weight, BMI, history, cumulative illness rating scale CIRS and menopausal status collected.

Furthermore, routine abdominal CT imaging will be performed in all patients. Finally, patients are requested to answer a validated questionnaire, the Green climacteric scale enquiring into presence of menopausal symptoms, and are asked to answer three questions on their physical activity level.

At timepoint 2 T2 subjects will undergo the clinically indicated surgical procedure. At start of surgery, a fasting blood draw will be obtained to measure oestrogen levels and systemic inflammation markers.

During surgery subcutaneous adipose tissue and visceral adipose tissue fat apron and intestinal epiploic fat as well as tumour where applicable will be collected, and snap frozen. At timepoint 3 T3 4 to 6 weeks postoperatively, another fasting blood draw is obtained for measurement of oestrogen levels and systemic inflammation markers.

In case of a recent infection the blood draw will be postponed until 10 days after the end of the infection. In case of adjuvant therapy, the postoperative blood draw will be performed latest at start of the adjuvant therapy. Finally, subjects will be asked to fill in the Green climacteric scale questionnaire a second time.

For subjects with the diagnosis of EC clinical follow-up data will be collected during 3 years T4. Using the abdominal CT-scans, abdominal fat volumes will be segmented and quantified using a semi-automatic dedicated software iNtuition, TeraRecon Inc.

San Mateo, CA, USA [ 20 , 30 ]. The biospecimens will be temporarily stored prior to use in this study at the MUMC Biobank [ 31 ]. In the Biobank Information System BIS type, date and volume of each specimen is recorded. A selection of steroid hormones including oestrogens, androgens, progestogens and corticosteroids as well as local adiponectin, resistin, leptin will be determined in the collected adipose tissue.

Inflammatory markers both locally in fat tissue macrophages, T cells: TNF-α, IL-6, and IL-1β and systemically blood including C-reactive protein CRP , interleukin 1 beta IL1β , interleukin 6 IL6 , tumour necrosis factor alpha TNFα , insulin-like growth factor 1 IGF1 , will be determined.

Tongjian You, Distributionn Immune support pills. Ryan, Barbara J. The Fat distribution and inflammation of this study was to investigate whether Oxidative stress pathways fitness, body composition, distributikn fat distribution, and Distrribution are different in obese distributkon women with and without the metabolic syndrome MSand whether the severity of MS is associated with these characteristics. Fifty-eight women age, 59 ± 1 yr; body mass index, Lean mass The number of MS components was directly related to weight, body mass index, fat mass, lean mass, visceral fat area, and plasma sTNFR1. Annemarie Koster, Sari Stenholm, Dawn Inflammztion. Alley, Lauren Immune support pills. Kim, Eleanor M. Simonsick, Alka M. Kanaya, Marjolein Visser, Denise K. Houston, Barbara J. Nicklas, Frances A.