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Ep. 109: Chris Palmer's “Brain Energy”, Type 1 Diabetes, and Low-Fat Diets For Weight Loss (Q \u0026 A)Subcutaneous fat metabolism -
In effect, in 13 lean males, Abate et al. If only one scan is used to measure the visceral adipose tissue area, a strictly defined longitudinal level is very important since the average visceral adipose tissue area shifts if there is a change in position, even of a few centimeters.
This, according to Sjöström et al. Instead, the longitudinal level must be defined in a strict relation to the skeleton, usually between the L4 and L5 vertebrae.
The subjects are examined in a supine position with their arms stretched above their heads. The choice to perform the scan at the level of the umbilicus was initially proposed by Borkan et al. Subsequently, Tokunaga et al. In addition to the recommendations of the Japanese investigators, studies from Korea 20 and from our clinic use the scan at the umbilicus.
Visceral fat is defined as intraabdominal fat bound by parietal peritoneum or transversalis fascia, excluding the vertebral column and the paraspinal muscles; subcutaneous fat is fat superficial to the abdominal and back muscles.
Subcutaneous fat area is calculated by subtracting the intraabdominal fat area from the total fat area. In addition, visceral fat increases with age Figure 1 shows cross-sectional abdominal areas obtained by CT at the level of the umbilicus in two women matched for the same BMI, who differed markedly in the accumulation of fat in the abdominal cavity but less so in the subcutaneous abdominal fat.
Computed tomography showing cross-sectional abdominal areas at umbilicus level in two patients demonstrating variation in fat distribution. A, Visceral type yr-old female, B, Subcutaneous type yr-old female, In obese subjects the level of the umbilicus can change from one patient to another, thus changing the visceral adipose tissue area; therefore, it is advisable that the scan area be defined in strict relation to the skeleton.
Chowdhury et al. However, the values for abdominal cut-off points were related to increased cardiovascular risk Table 2. Using the scan at the umbilicus as described by several investigators gave results similar to, although somewhat lower than, those reported using the L4-L5 level.
Abdominal visceral adipose tissue area cut-off points related to increased cardiovascular risk. Regarding the relationship between the modifications in subcutaneous and visceral adipose tissue, with changes in body weight, it was shown that after severe weight loss, subcutaneous fat at the abdominal level is lost in greater proportion than visceral fat, but the mechanism of these differential changes in both compartments of abdominal fat is unknown, suggesting that visceral fat does not reflect nutritional status to the extent that sc fat does In the same way, published data suggest that, at least in relative terms, visceral fat increases less than subcutaneous fat with increased body weight However, because the amount of subcutaneous abdominal fat is calculated indirectly, it is likely that significant measurement error could be introduced Regarding the reproducibility of CT measurement of visceral adipose tissue area, Thaete et al.
The duplication occurred after the initial scan; the subjects were repositioned before repeat scanning. As indicated in the Introduction , individuals with a high accumulation of visceral abdominal fat, as shown by CT scans, had an increased risk for development of type 2 diabetes, dyslipidemia, and coronary heart disease.
Table 2 shows the thresholds above which metabolic complications would be more likely to be observed in visceral adipose tissue areas. Desprès and Lamarche 73 , Hunter et al. They found that a value above cm 2 was associated with an increased risk of coronary heart disease in pre and postmenopausal women 75 ; the same group 74 found that males with abdominal visceral fat cross-section areas measuring more than cm 2 were clearly at an increased risk for coronary disease.
On the other hand, Desprès and Lamarche 73 found that in both men and women a value of cm 2 was associated with significant alterations in cardiovascular disease risk profile and that a further deterioration of the metabolic profile was observed when values greater than cm 2 of visceral adipose tissue were reached.
From the same center, Lemieux et al. It was concluded that waist circumference was a more convenient anthropometric correlate to visceral adipose tissue because its threshold values did not appear to be influenced by sex or by the degree of obesity.
Anderson et al. The most extensive studies using a single CT scan at umbilical level was done by Matsuzawa and colleagues 17 , However, they did not present the raw data on visceral and subcutaneous areas but only their ratios, thus precluding their inclusion in Table 2.
In another study, performed in Japan by Saito et al. Lottenberg et al. Magnetic resonance imaging MRI. MRI provided results similar to CT without exposure to ionizing radiation, the main problem with CT multislice measurements.
It demonstrated good reproducibility for total and visceral adipose tissue volumes 63 , which were slightly lower than previously reported using CT 55 , although the percent contribution of visceral to total adipose tissue volume was similar 18 vs. Subcutaneous adipose tissue and visceral fat areas at the L4-L5 level determined in 27 healthy men by MRI were These areas were highly predictive of the corresponding volume measurements computed from the scan MRI, confirming the CT studies of Kvist et al.
Two studies have compared estimates of subcutaneous and visceral adipose tissue by CT and MRI. Comparison between MRI and CT in seven subjects showed a high degree of agreement in measurement of total subcutaneous adipose tissue area but not visceral adipose tissue area As already mentioned, MRI has been validated in three cadavers, confirming its accuracy Ultrasound US.
US subcutaneous and intraabdominal thicknesses, the latter corresponding to the distance between abdominal muscle and aorta, were measured 5 cm from the umbilicus on the xipho-umbilical line with a 7.
The intraindividual reproducibility of US measurements was very high both for intraabdominal and subcutaneous thickness as well as for interoperators 83 , Several studies demonstrated a highly significant correlation between the intraabdominal adipose tissue determined by CT and by US.
A decade ago, Armellini et al. In a more recent study, Tornaghi et al. In a study of men C. Leite, D. Matsuda, B. Wajchenberg, G. Cerri, and A. Halpern, unpublished data , in which In obese women, after a 6-kg weight loss, a significant decrease was found in intraabdominal fat but not in subcutaneous adipose tissue, as determined by both CT and US There was also a significant correlation between changes in intraabdominal adipose tissue using both techniques, indicating that US can be used in the evaluation of body fat distribution modifications during weight loss.
This is another confirmation of the reliability of the US intraabdominal determinations. The amount of visceral fat increases with age in both genders, and this increase is present in normal weight BMI, In a study of subjects 62 males and 68 females with a wide range of age and weight , Enzi et al.
This fat topography was retained in young and middle-aged females up to about 60 yr of age, at which point there was a change to an android type of fat distribution.
This age-related redistribution of fat is due to an absolute as well as relative increment in visceral fat depots, particularly in obese women, which could be related to an increase in androgenic activity in postmenopausal subjects. On the other hand, they showed that males at any age tend to accumulate fat at the visceral depot, increasing with age and BMI increase.
In the male, a close linear correlation between age and visceral fat volume was shown, suggesting that visceral fat increased continuously with age Although this correlation was also present in women, the slope was very gentle in the premenopausal condition.
It became steeper in postmenopausal subjects, almost the same as in males Further, Enzi et al. From the published data 68 , 90 , it can be concluded that both subcutaneous and visceral abdominal fat increase with increasing weight in both sexes but while abdominal subcutaneous adipose tissue decreases after the age of 50 yr in obese men, it increases in women up to the age of 60—70 yr, at which point it starts to decline Fowler et al.
Finally, as previously indicated, visceral fat is more sensitive to weight reduction than subcutaneous adipose tissue because omental and mesenteric adipocytes, the major components of visceral abdominal fat, have been shown to be more metabolically active and sensitive to lipolysis Lemieux et al.
In addition, the adjustment for differences in visceral fat between men and women eliminated most of the sex differences in cardiovascular risk factors. There is evidence supporting the notion that abdominal visceral fat accumulation is an important correlate of the features of the insulin-resistant syndrome 23 , 24 , 29 but this should not be interpreted as supporting the notion of a cause and effect relationship between these variables This subject will be discussed later on.
The correlations of abdominal visceral fat mass evaluated by CT or MRI scans with total body fat range from 0. They tend to be lower in the lean and normal weight subjects than in the obese As indicated by Bouchard et al.
When they examined the relationship of total body fat mass to visceral adipose tissue accumulation in men and in premenopausal women, Lemieux et al.
Furthermore, the relationship of visceral adipose tissue to metabolic complications was found to be independent of concomitant variation in total body fat, and it was concluded that the assessment of cardiovascular risk in obese patients solely from the measurement of body weight or of total body fatness may be completely misleading 19 , 22 , 36 , Indeed, it appears that only the subgroup of obese individuals characterized by a high accumulation of visceral adipose fat show the complications predictive of type 2 diabetes and cardiovascular disease On the other hand, after adjustment for total body fat, Abate et al.
Intraabdominal visceral fat is associated with an increase in energy intake but this is not an absolute requirement. Positive energy balance is a strong determinant of truncal-abdominal fat as shown by Bouchard and colleagues 96 in overfeeding experiments in identical twins.
The correlations between gains in body weight or total fat mass with those in subcutaneous fat on the trunk reached about 0. In contrast, these correlations attained only 0. Thus, positive energy balance does not appear to be a strong determinant of abdominal visceral fat as is the case with other body fat phenotypes 7.
In effect, as discussed in the CT section of imaging techniques for evaluation of intraabdominal visceral fat, some investigators 70 , 71 have shown that either when the subjects lose or increase their weight, particularly females, visceral fat is lost or gained, respectively, less than subcutaneous fat at the abdominal level.
However, at variance from these data, Zamboni et al. Similarly, as already mentioned, Smith and Zachwieja 32 noted that all forms of weight loss affect visceral fat more than subcutaneous fat percentage wise , and there was a gender difference, with men appearing to lose more visceral fat than women for any given weight loss.
LPL activity, being related to the liberation of the lipolytic products [from chylomicra and very-low-density lipoproteins VLDL ] to the adipocytes for deposit as triglycerides, is a key regulator of fat accumulation in various adipose areas, since human adipose tissue derives most of its lipid for storage from circulating triglycerides.
However, adipocytes can synthesize lipid de novo if the need arises, as in patients with LPL deficiency According to Sniderman et al. The increase of visceral fat masses with increasing total body fat was explained by an increase of fat cell size only up to a certain adipocyte weight. However, with further enlargement of intraabdominal fat masses with severe obesity, the number of adipocytes seems to be elevated , In women, but not in men, omental adipose tissue has smaller adipocytes and lower LPL activity than subcutaneous fat depots since variations in LPL activity parallel differences in fat cell size 7.
When adipocytes enlarge in relation to a gain in body weight, the activity of LPL increases in parallel, possibly as a consequence of obesity-related hyperinsulinism. The higher basal activity of adipose tissue LPL in obesity is accompanied by a lower increment after acute hyperinsulinemia Lipid accumulation is favored in the femoral region of premenopausal women in comparison with men In the latter, LPL activity as well as the LPL mRNA levels were greater in the abdominal than in gluteal fat cells, while the opposite was observed in women, suggesting that regional variation of gene expression and posttranslational modification of LPL could potentially account for the differences between genders in fat distribution With progressive obesity, adipose tissue LPL is increased in the depots of fat in parallel with serum insulin.
However, when obese subjects lost weight and became less hyperinsulinemic, adipose LPL increased further and the patients who were most obese showed the largest increase in LPL, suggesting that very obese patients are most likely to have abnormal LPL regulation, independent of the influence of insulin.
In response to feeding, the increase in LPL is, as indicated, due to posttranslational changes in the LPL enzyme. However, the increased LPL after weight loss involved an increase in LPL mRNA levels, followed by parallel increases in LPL protein and activity Because the response to weight loss occurred via a different cellular mechanism, it is probably controlled by factors different from the day-to-day regulatory forces.
In addition, because the very obese patients demonstrated a larger increase in LPL with weight loss than the less obese patients, these data suggest a genetic regulation of LPL that is most operative in the very obese The role of sex steroids, glucocorticoids, and catecholamines in the regulation of adipose tissue LPL activity in various fat depots will be discussed in the section on hormonal regulation of abdominal visceral fat.
Lipid mobilization and the release of FFA and glycerol are modulated by the sympathetic nervous system. Catecholamines are the most potent regulators of lipolysis in human adipocytes through stimulatory β l - and β 2 -adrenoreceptors or inhibitoryα 2-adrenoreceptors A gene that codes for a third stimulatory β -adrenoreceptor, β 3 -adrenoreceptor, is functionally active principally in omental adipocytes but also present in mammary fat and subcutaneous fat in vivo In both genders and independently of the degree of obesity, femoral and gluteal fat cells exhibit a lower lipolytic response to catecholamines than subcutaneous abdominal adipocytes, the latter showing both increased β l - and β 2 -adrenoreceptor density and sensitivity and reduced α2-adrenoreceptor affinity and number Refs.
The increased sensitivity to catecholamine-induced lipolysis in omental fat in nonobese individuals is paralleled by an increase in the amount of β l - and β 2 -receptors, with normal receptor affinity and normal lipolytic action of agonists acting at postadrenoreceptor steps in the lipolytic cascade , ; this is associated with enhanced β 3 -adrenoreceptor sensitivity, which usually reflect changes in receptor number in comparison with subcutaneous adipocytes , Comparison of lipolysis, antilipolysis, and lipogenesis in omental and subcutaneous fat in nonobese and obese individuals.
Adipocytes from obese subjects generally show increased lipolytic responses to catecholamines, irrespective of the region from which they are obtained, and enhanced lipolysis in abdominal compared with gluteo-femoral fat 21 , The antilipolytic effect is also reduced in vitro in obesity, both in omental and subcutaneous adipocytes The typical features of visceral fat, e.
An increased β 3 -adrenoreceptor sensitivity to catecholamine stimulation may lead to an increased delivery of FFA into the portal venous system, with several possible effects on liver metabolism. These include glucose production, VLDL secretion, and interference with hepatic clearance of insulin , resulting in dyslipoproteinemia, glucose intolerance, and hyperisulinemia.
Lönnqvist et al. They observed that males had a higher fat cell volume with no sex differences in the lipolytic sensitivity to β l - and β 2 -adrenoreceptor-specific agonists or in the antilipolytic effect of insulin.
However, the lipolytic β 3 -adrenoreceptor sensitivity was 12 times higher in men, and the antilipolytic α2-adrenoreceptor sensitivity was 17 times lower in men.
It was concluded that in obesity, the catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat cell volume, a decrease in the function ofα 2-adrenoceptors, and an increase in the function of β 3 -adrenoreceptors.
These factors may contribute to gender-specific differences observed in the metabolic disturbances accompanied by obesity, i. Glucocorticoid receptors. Glucocorticoid receptors, one of the most important receptors for human adipose tissue function, are involved in metabolic regulation and distribution of body fat under normal as well as pathophysiological conditions.
Glucocorticoid receptors in adipose tissue show a regional variation in density with elevated concentrations in visceral adipose tissue In spite of the lower receptor density, the elevated cortisol secretion results in clearly increased net effects of cortisol.
Androgen and estrogen receptors. Adipocytes have specific receptors for androgens, with a higher density in visceral fat cells than in adipocytes isolated from subcutaneous fat.
Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cells , thereby affecting lipid mobilization. This is more apparent in visceral fat omental, mesenteric, and retroperitoneal because of higher density of adipocytes and androgen receptors, in addition to other factors However, at variance with the effects of testosterone, dihydrotestosterone treatment does not influence lipid mobilization In females, there is an association between visceral fat accumulation and hyperandrogenicity, despite the documented effects of testosterone on lipid mobilization and the expected decrease in visceral fat depots.
The observation that visceral fat accumulation occurs only in female-to-male transsexuals after oophorectomy suggests that the remaining estrogen production before oophorectomy was protective The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue.
However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects. Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors.
While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role.
However, GH is clearly involved in the regulation of visceral fat mass in humans. Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors.
Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels.
Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue.
Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7. Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot However, despite strong antilipolytic effect of adenosine analogs, human adipocytes contain few adenosine type A l receptors, regardless of the fat depot considered According to Arner , the α2-, β l -,β 2 -, and β 3 -adrenoreceptors and receptors for insulin, adenosine, and glucocorticoids, as well as for PGE 2 , a potent antilipolytic agent with high affinity receptors identified in adipocytes , have a major functional role, as shown by relevant biological receptor-mediated effects, the presence of a receptor molecule, and receptor regulation.
The receptors for GH, thyroid hormones, estrogen, and testosterone, as well as for acetylcholine and TSH, probably have an important functional role but complete evidence, indicated in the previous group of receptors, is not present so far; however, there is little doubt of a regulatory role.
Genetic epidemiology: heritability and segregation analysis. Studies performed in individuals from families of French descent living in Quebec City [Quebec Family Study QFS ] allowed the estimation of the fraction of the phenotypic variance that could be attributed to the genetic and environmental factors among the obesity phenotypes or in the distribution of the adipose tissue, taking into account the BMI and amount of subcutaneous fat by the sum of the measurement of skinfolds in six different sites , lean body mass, fat mass, percentage of fat derived from underwater weighing, and visceral fat by CT , The residual variance corresponded to environmental factors, but some factors cultural, nongenetic could be transmitted from parents to descendents and sometimes were confounded by genetic effects Segregation analysis studies have recently concluded that visceral fat is similarly influenced by a gene with a major effect in the QFS and HERITAGE families , However, after adjustment of the visceral adipose tissue for the fat mass, the effect of the gene with the major effect was not more compatible with a mendelian transmission.
These results suggested the presence of a pleiotropism: the gene with the major effect, identified by the fat mass , could similarly influence the amount of visceral fat Similar results were obtained with the same type of analysis in the HERITAGE cohort To test the hypothesis of a genetic pleiotropism, Rice et al.
The results of this study Fig. These results have confirmed the presence of a genetic pleiomorphism and suggested the presence of genes affecting simultaneously the amounts of fat mass and visceral abdominal fat.
Schematic representation of the genetic effects on total fat mass and visceral fat adjusted for the fat mass and on the co-variation between the two phenotypes Quebec Family Study, G 1 and G 2 represent the genetic effects specific for the total fat mass and visceral fat, respectively.
E 1 and E 2 represent the specific effects of the environment on total fat mass and visceral fat, respectively.
G 3 and E 3 indicate the genetic and environment effects common to both phenotypes. Pérusse et al. The interactions of the effects of genotype and environment evaluated in monozygotic twins, when the energy balance is manipulated, indicated that even though there were large interindividual differences in the response to excess or negative energy balance, there was a significant within-pair resemblance in response 96 , In effect, in response to overfeeding, there was at least 3 times more variance in response between pairs than within pairs for the gains in body weight, fat mass, and fat-free mass In relation to the response to the negative energetic balance, at least 7 times more variation was observed in response between pairs than within members of the same pair of twins, with respect to the same variables This intrapair similarity in the response to either excess or deficient energy balance is also observed in relation to the abdominal visceral fat Thus, the interaction between genotype and environment is important to consider in the study of the genetics of obesity since the propensity to fat accumulation is influenced by the genetic characteristics of the subject.
Molecular genetics: association and linkage studies. Several candidate genes as well as random genetic markers were found to be associated with obesity as well as body fat and fat distribution in humans.
The current human obesity gene map, based on results from animal and human studies, indicates that all chromosomes, with the exception of the Y chromosome, include genes or loci potentially involved in the etiology of obesity Initial findings from the QFS showed that significant but marginal associations with body fat were found with LPL and the α2-subunit of the sodium-potassium ATPase genes The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight This mutation was also shown to be associated with abdominal visceral obesity in Japanese subjects, with lower triglycerides in the Trp64Arg homozygotes but not heterozygotes It has been suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.
On the other hand, Vohl et al. Previously, it was reported by the same group that apo-B gene Eco R-1 polymorphism appeared to modulate the magnitude of the dyslipidemia generally found in the insulin-resistant state linked with visceral obesity These studies are a demonstration of a significant interaction between visceral obesity and a polymorphism for a gene playing an important role in lipoprotein metabolism.
When the genes related to the hormonal regulation of body fat distribution studied in the QFS families sex hormone-binding globulin, 3β-hydroxysteroid dehydrogenase, and glucocorticoid receptor genes were considered along with the knowledge that body fat distribution is influenced by nonpathological variations in the responsiveness to cortisol, it was shown that the less frequent 4.
However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level. The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method.
One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above.
The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans.
This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified.
The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol.
These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue. The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system.
As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides. LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells.
The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat.
With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography.
In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women.
The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot.
Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP.
ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described. Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a.
Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase.
As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so. In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role.
The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen.
The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP.
However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts. Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature.
As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP.
Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins. In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile.
Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat.
Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis.
It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis. The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels.
Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes.
Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients.
In effect, the reduction of PAI-1 after weight loss related more to the degree of weight reduction than to triglyceride or insulin changes, as above indicated, and the lack of increase of PAI-1 in type 2 diabetics without obesity , strongly suggesting that visceral fat is an important contributor to the elevated plasma PAI-1 level observed in visceral obesity independent of insulin, triglyceride, and glucose level.
Finally, prospective cohort studies of patients with previous myocardial infarction or angina pectoris have underlined the association between an increase in plasma PAI-1 levels and corresponding defective fibrinolysis and the risk of atherosclerosis and thrombosis, particularly in relation to coronary events , thus linking visceral fat accumulation to macrovascular disease Recently, it was shown that in addition to insulin, corticosteroids dexamethasone and hydroxycorticosterone affect PAI-1 synthesis by human subcutaneous adipose tissue explants in a dose-dependent manner; this model showed the regulation of PAI-1 by adipose tissue after validation by showing a high correlation between the production of PAI-1 by omental and subcutaneous fat In the same way, it was demonstrated that PAI-1 production was significantly correlated with that of tumor necrosis factor-α TNFα , emphasizing a possible local contribution of TNFα in the regulation of PAI-1 production by human adipose tissue P aromatase activity in adipose tissue is important for estrogen production, which may have a paracrine role, since, as previously indicated, estrogen receptors are expressed in human adipose tissue In effect, estrone, the second major human circulating estrogen in premenopausal women and the predominant one in postmenopausal women, is mostly derived from the metabolism of ovarian-secreted estradiol catalyzed by 17β-hydroxy steroid dehydrogenase and from aromatization of androstenedione in adipose tissue in the former and almost exclusively by aromatization of that C19 androgen secreted by the adrenals in the latter.
The peripheral aromatization of testosterone to estradiol and estrone contributes minimally to estradiol and estrone production The conversion rate of androstenedione to estrone increases as a function of aging and obesity [due to an increase in adipose tissue P aromatase transcript levels, highest in the buttocks, next highest in the thighs, and lowest in the subcutaneous abdominal tissue , ] and significantly greater in women with lower gynoid obesity than in upper body obesity In obese men, the peripheral conversions of testosterone to estradiol and androstenedione to estrone, as well as the circulating levels of those estrogens, are also increased in proportion to the degree of obesity , However, only plasma levels of estrone had a significant correlation with CT-derived abdominal visceral fat and femoral areas Since the increased metabolism of testosterone to estradiol did not account for the major increase in estradiol production in obese men , it is probable that estradiol is secreted or is produced from the peripheral conversion of estrone, as observed in postmenopausal women.
The most abundant adrenal steroid, dehydroepiandrosterone sulfate DHEA-S can also form the active sex steroids, dihydrotestosterone and estradiol, in several tissues, including mesenteric fat The active androgens and estrogens made locally in peripheral tissues, especially adipose fat, exert their action by interacting with the corresponding receptors in the same or nearby cells where their synthesis took place before being released in the extracellular environment as such or as inactive metabolites.
The aromatase enzyme responsible for transforming androstenedione into estrone is present in nonendocrine tissues, particularly adipocytes and adipose stromal cells, the level of aromatase activity in stromal cells being greater than that in adipocytes Insulin and cortisol independently induce preadipocyte differentiation with both having a synergistic effect The intrinsic gender differences in preadipocytes could contribute to a gender-specific pattern of fat distribution Leptin is the product of the obesity ob gene, which is expressed in adipocytes , The human ob gene spans approximately 20 kb and exists in a single copy on chromosome 7q Several studies in rodents suggest that leptin acts as a signaling factor from adipose tissue to the central nervous system, regulating food intake and energy expenditure.
It is hypothesized that via this leptin feedback loop, homeostasis of body weight and a constant amount of body fat are achieved In humans, a strong positive correlation is observed between serum leptin levels and the amount of body fat and adipocyte leptin mRNA as in rodents , The results are in accordance with the in vitro data indicating that leptin secretion is a reflection of fat hypertrophy.
The adipocyte is the only known source of the ob gene product, leptin, as the preadipocytes do not present this capacity The subcutaneous-omental ratio of leptin mRNA expression was markedly higher in women than in men.
Part of the results, according to the authors, could be explained, particularly in women, by the fact that subcutaneous adipocytes are larger than omental adipocytes and as adipocytes increase in size, the leptin mRNA is up-regulated such that it forms a greater proportion of the total mRNA than in smaller adipocytes.
Indeed, increased leptin mRNA expression in large adipocytes has been reported by Hamilton et al. Furthermore, leptin expression and levels increase as the size of the adipose tissue triglyceride stores increase In a study examining the secretion of leptin in subcutaneous and omental fat tissue from obese and nonobese women, it was shown that the leptin secretion rate and leptin mRNA expression were about 2 to 3 times higher in the subcutaneous than in the omental fat tissue in both obese and nonobese subjects.
There was a positive correlation between BMI and leptin secretion rates in subcutaneous and omental fat tissue. Furthermore, leptin secretion rates in both fat tissues had a high positive correlation with serum leptin levels.
Serum leptin circulates, in part, bound to transport proteins in the serum of both rodents and humans, and the size distribution of endogenous serum leptin, as determined by RIA after sucrose gradient centrifugation, is consistent with saturation of binding in hyperleptinemic obesity. Thus, in humans, free leptin increases with BMI For individuals with the same BMI, the leptin circulating levels can vary by 1 order of magnitude , suggesting that leptin is regulated by factors other than the size of the adipose tissue depot.
In effect, the secretion of leptin by adipocytes is regulated by nutritional and hormonal factors. Acute changes in energy balance appear to regulate leptin expression and circulating levels. On the other hand, both leptin expression and levels decline rapidly in response to starvation, with serum leptin levels starting to decline after 12 h of fasting and reaching a nadir after 36 h, out of proportion to body adiposity changes , Thus, under conditions of steady-state energy balance, leptin is a static index of the amount of triglyceride stored in adipose tissue and in non-steady-state energy balance situations.
Leptin may be acutely regulated independently of the available adipose tissue triglyceride stores and may serve as a sensor of energy balance However, the precise mechanism mediating the distinct responses to changes in body adiposity and energy balance remains to be elucidated.
In rodents, the decreased ob gene expression after fasting and increase after realimentation appear to be related, according to in vitro data, to a transcriptional direct effect of insulin , , In humans, the positive effects of insulin are controversial in vivo.
Experiments in vitro have not solved the controversy over the potential effects of insulin on leptin synthesis, as both an increase and no change have been reported Dose-response and time-course characteristics of the effect of insulin on plasma leptin in normal men during a 9-h euglycemic clamp indicated that physiological insulinemia acutely increases leptin by comparison with a control saline infusion.
Plasma leptin also showed a dosage-dependent increase during the insulin infusion The hormonal regulation glucocorticoids and insulin of leptin synthesis was studied by Halleux et al. They found that glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat.
This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene. 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.
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.
Methods cat assessment, e. The correlation of fat distribution with age, Boost cognitive processing speed, total body fat, energy balance, adipose Risk factors of performance-enhancing substances metbaolism lipase and lipolytic activity, adipose tissue Healthy eating habits, and genetic characteristics are discussed. Several secreted metabolisj expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented. Anthropometric indexes of abdominal visceral adipose tissue mass.Subcutaneeous you for faat nature. You are metaboliam a browser Leafy greens benefits with Boost cognitive processing speed support for CSS.
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Download references. The authors Boost cognitive processing speed Ginseng for overall wellness from The Cat Research Council, European Research Council, Boost cognitive processing speed Diabetes Association, Swedish Foundation for Strategic Research, Metwbolism Diabetes Meatbolism Boost cognitive processing speed at Karolinska Institutet, Stockholm County Council and Novo Nordisk Foundation.
Department of Physiology and Pharmacology, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, Stockholm, SE 77, Sweden.
Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, Stockholm, SE 77, Sweden. You can also search for this author in PubMed Google Scholar. Correspondence to Juleen R. Reprints and permissions.
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Learn more. Figure 1: Exercise training remodels subcutaneous adipose tissue and improves glucose homeostasis. References Egan, B. Article CAS Google Scholar Wallberg-Henriksson, H. CAS PubMed Google Scholar Hawley, J.
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Acknowledgements The authors acknowledge funding from The Swedish Research Council, European Research Council, Swedish Diabetes Association, Swedish Foundation for Strategic Research, Strategic Diabetes Research Program at Karolinska Institutet, Stockholm County Council and Novo Nordisk Foundation.
Author information Authors and Affiliations Department of Physiology and Pharmacology, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, Stockholm, SE 77, Sweden Harriet Wallberg-Henriksson Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, Stockholm, SE 77, Sweden Juleen R.
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: Subcutaneous fat metabolism| REVIEW article | Blood samples metaboljsm drawn in the morning hours after a h overnight Subcutaneeous. This uSbcutaneous in a higher Subcutaneius ratio Subcutaneous fat metabolism women compared with men 1. Rosen, E. Antioxidant-rich foods adipose tissue VAT is an important factor in the development of nonalcoholic fatty liver disease NAFLDalso seen as the hepatic equivalent of metabolic syndrome, both in men and women. Adipose tissue also known as body fat or simply fat is a loose connective tissue composed mostly of adipocytes. Obese individuals express 2. Correspondence to Ju-hye Chung. |
| Exercise remodels subcutaneous fat tissue and improves metabolism | Overweight and obesity in the United States: prevalence and trends, Despite body composition differences, an inverse nonlinear relationship was observed between glucose disposal and visceral fat independent of sex; the slope and intercept were not different in men and women. However, in obesity, changes occur in adipocytes that conceivably try to offset the detrimental effects of accelerated lipolysis. Prostaglandins, Leukotrienes, and Essential Fatty Acids. Miyazaki Y , Glass L , Triplitt C , Wajcberg E , Mandarino LJ , DeFronzo RA. Leonardus Antonius Bernardus Joosten. Spend some time with your doctor to determine the proper amount of fat for you and — if you are not at your ideal level — to help put together a diet and activity plan for optimum health. |
| Relevant articles | Glucose disposal Risk factors of performance-enhancing substances activated BAT occurs Glycemic load and immune health both insulin-dependent and insulin-independent Subchtaneous This is metaolism by several studies Subcuaneous that BMI and adiposity positively correlate with circulating FGF21 Subcutameous in Sjbcutaneous and humans — Obes Res. reported a correlation between resistin levels and BMI and SAT [ 37 ], other studies found no association between resistin levels and obesity [ 3839 ] or SAT [ 40 ]. Stored triglycerides are therefore in a constant state of flux, whereby energy storage and energy mobilization are determined largely by hormonal fluctuations. |
| Exercise remodels subcutaneous fat tissue and improves metabolism | Nature Reviews Endocrinology | These areas were highly predictive of Subcutaneous fat metabolism corresponding ft measurements computed from the scan MRI, confirming Subcutaheous CT studies of Kvist Subcutaneous fat metabolism al. Metaboliem Boost cognitive processing speed that managing stress may help Subcutanekus the effort Isotonic drink options shed subcutaneous fat. Cross-sex hormone administration in transsexual subjects showed that subjects with high circulating testosterone, whether male or female, had significantly lower serum leptin at a certain degree of body fatness compared with subjects male or female with high estrogen and low testosterone levels. also used microarray analysis to demonstrate that insulin deficiency inhibits the differentiation of beige adipocytes but does not disturb their capacity for browning. Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cellsthereby affecting lipid mobilization. |
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