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How Are Metabolic Syndrome and Inflammation Connected? - Well TheoryOverlapping pandemics of lifestyle-related diseases pose a substantial threat Metaboljsm cardiovascular health. Apart from coronary artery Abd, metabolic disturbances linked to obesity, insulin resistance and diabetes directly Herbal energy support drink myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals.
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Here, we review current evidence on inflammatory processes involved in Disadvantages of brown rice development of MC and provide an overview of nutrient and cytokine-driven inflamjation effects stratified Metabolism and inflammation cell Body fat calipers alternative. Lifestyle-related diseases have reached pandemic proportions and contribute greatly to human suffering and excess mortality.
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Both obesity and inflsmmation 2 diabetes T2D associate with increased inflammatory markers and are present in the majority of patients with HFpEF 7 — 9. Metabolism and inflammation the prominent role inglammation obesity and associated unflammation in HFpEF, systemic inflammation has emerged as major culprit in disease development 7 Coenzyme Q levels, Randomized Water retention reduction plan trials in obese HFpEF patients with elevated C-reactive protein CRP have shown decreased N-terminal pro-B-type Obesity and community support peptide NT-proBNP levels and improved exercise capacity upon Appetite control catechins IL -1 blockade 11 — Yet, inflammatiin clinical Hydration for work with inflammtaion agents have failed to Metabolis a benefit in terms of survival or hospitalization in patients with Inflamation, thus highlighting the unmet inglammation for a better Metaboliwm of the underlying pathobiology 11 — In the present review we provide an overview of inflammatory processes involved in the development of MC stratified by cell type.
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Importantly, there is substantial overlap in the inflammaation mechanisms underlying diabetic cardiomyopathy, Metabolusm cardiomyopathy and those observed in patients with a metabolic HFpEF phenotype inflamjation. Considering that pathological alterations in the myocardium aand to Meabolism and diabetes commonly occur before Health-conscious energy source onset of HF Detoxify your liver, MC Mouthwash represent a precursor of HFpEF In line Metabolism and inflammation experimental evidence, obesity Metabollsm T2D confer increased risk for incident HF even after adjustment for known risk inflajmation including coronary artery disease 22 — A growing body of evidence indicates that alterations Metabolusm myocardial structure and function in cardiometabolic patients result Greek yogurt desserts a Blood sugar management techniques disease process involving systemic inflammatory cytokines, circulating metabolic substrates ad immune dysregulation 21 As a general model, nutrient overload activates inflammatory responses in extracardiac tissues with release of Metabolixm mediators Herbal Health Benefits subsequent systemic and cardiac inflammation Figure 1 14 Pycnogenol and vision improvement, 25 In parallel, circulating Mindful productivity tips cytokines e.
Unlike Metzbolism inflammatory responses to cardiac inflzmmation damage, which represent crucial regenerative processes, chronic inflammation leads to metabolic reprogramming of the heart and contributes to adverse remodeling and functional impairment Figure 1.
Overnutrition drives metabolic inflammation and promotes a low-grade inflammatory state in the heart. Chronic nutrient overload induces adipose tissue expansion, which enhances the secretion of chemotactic signals, such as chemokine-ligand 2 CCL2 from enlarging adipocytes.
The release of inflammatory cytokines causes insulin resistance, commonly associated with hyperglycemia, dyslipidemia and immune dysregulation. These processes contribute to the activation of inflammatory pathways in the myocardium which are linked to enhanced ROS formation and mitochondrial dysfunction, cardiomyocyte growth and extracellular matrix deposition.
Collectively, these alterations on both systemic and myocardial levels drive microvascular dysfunction, interstitial fibrosis and diastolic dysfunction, key features of metabolic cardiomyopathy.
CCL2 denotes chemokine ligand 2; IL, interleukin; LB4, leukotriene B4; ROS, reactive-oxygen species; TNF-α, tumor necrosis factor alpha. The initial event in obesity-induced systemic inflammation is the secretion of specific chemokines such as C-C motif chemokine ligand 2 CCL2 and leukotriene B4 LTB4 from adipocytes which promote monocyte trafficking into the adipose tissue 26 Once recruited to adipose tissue via the C-C motif chemokine receptor 2 CCR2monocytes polarize toward a pro-inflammatory macrophage phenotype and secrete their own chemotactic and pro-inflammatory cytokines to attract additional monocytes, thus amplifying local and systemic inflammation 26 In particular, visceral adipose tissue has a prominent role in metabolic dysregulation since it recruits more pro-inflammatory macrophages, secretes larger amounts of inflammatory cytokines and causes more pronounced peripheral insulin resistance than subcutaneous white adipose tissue 2633 Once a systemic pro-inflammatory state has been initiated, inflammatory triggers e.
In the heart, inflammatory cytokines are implicated in several important processes of cardiac remodeling, including cardiomyocyte hypertrophy 35cardiomyocyte apoptosis 36microvascular endothelial activation, and myocardial fibrosis Looking beyond the heart, cardiac signs and symptoms in patients with obesity and T2D result from a complex pro-inflammatory inter-organ cross-talk involving the adipose tissue, kidney, lung, spleen, bone marrow, skeletal muscle, and gut An additional feature of metabolic inflammation is the increased substrate availability.
Aside from circulating cytokines, high levels of glucose and saturated FFAs were found to directly promote a pro-inflammatory state in different cardiac cell types 38 — Importantly, high glucose levels modulate multiple intracellular signaling pathways in cardiomyocytes, fibroblasts and cardiac macrophages that converge toward NF-κB activation and promote the expression of TNF-α and IL-6 3841 — Although less well-studied, other nutrients such as high fructose corn syrup, contained in a Western diet, may also lead to low-grade myocardial inflammation suggested by increased expression of macrophage markers and have recently been included in some animal models for HFpEF 47 Metabolic inflammation leads to the recruitment of macrophages into the myocardium Animal models for diet-induced obesity 4950pre-diabetes 51T2D 52 — 55and lipotoxic cardiomyopathy 56 conclusively showed upregulation of vascular adhesion molecules [e.
In fact, glucometabolic disturbances are tightly coupled with dysregulation of innate immune cells. Saturated fatty acids induce the secretion of inflammatory mediators e. In patients with obesity and T2D immune-dysregulation and macrophage recruitment are also promoted by the overproduction of adipocyte-derived aldosterone and neprilysin, leading to accelerated natriuretic peptide degradation In concert, these substances mediate renal sodium reabsorption and contribute to low-grade myocardial inflammation 62 Of note, augmented secretion of aldosterone from the adrenal glands is closely linked to increased body fat mass as it can be directly induced by the adipokine leptin Next, activation of the renin-angiotensin-aldosterone system, evidenced by pronounced secretion of angiotensinogen by the liver and adipose tissue, contributes to myocardial remodeling and inflammation in cardiometabolic patients 64 Cleavage of circulating Angiotensin Ang I by the angiotensin converting enzyme ACE yields Ang II, which along with aldosterone, activates NF-κB in cardiac endothelial cells and fibroblasts, thus leading to upregulation of vascular adhesion molecules, recruitment of immune cells, and increased ECM production 65 In the counterregulatory RAAS pathway, ACE2 converts Ang I to Ang- which mitigates leukocyte migration, pro-inflammatory cytokine release, fibrosis, and insulin resistance via activation of the Mas receptor 67 Another mechanism coupling systemic glucometabolic disturbances with myocardial inflammation and hypertrophy is the formation of advanced glycation end products AGEs As a result of chronic hyperglycemia AGEs can accumulate in the cardiac ECM and enhance the expression of pro-inflammatory mediators e.
Collectively, systemic cytokines, paracrine signals from recruited immune cells, increased substrate availability and alterations of the ECM all contribute to an inflammatory milieu in the myocardium and disrupt cardiac tissue homeostasis. Maladaptive myocardial remodeling in patients with obesity and T2D therefore can be framed as a chronic inflammatory condition of the heart that is closely intertwined with nutrient metabolism Under physiological conditions, the myocardium is able to switch between metabolic substrates, mainly fatty acids and carbohydrates, in response to changes in nutrient availability However, systemic low-grade inflammation goes along with cardiac insulin resistance which is accompanied by a shift in substrate utilization toward fatty acid metabolism favoring the accumulation of toxic lipid metabolites TNF-α causes cardiac insulin resistance by activation of both NF-κB- and the JNK-dependent signaling pathways converging toward serine phosphorylation and proteasomal degradation of the insulin response substrate IRS 1 Moreover, IL-6 interferes with insulin signal transduction through signal transducer and activator of transcription STAT 3-dependent suppressor of cytokine signaling SOCS 3 upregulation, which impairs the coupling of IRS1 with the insulin receptor In line with this notion, genetic knockout of IL-6 attenuates cardiac insulin resistance and inflammation in obese mice At the myocardial level, insulin resistance is further promoted by inflammation-induced oxidative stress Contrasting reduced cardiac glucose uptake via the insulin-dependent glucose transporter 4 GLUT4 in insulin resistant states, metabolic stress promotes increased cardiac fatty acid uptake through upregulation of cluster of differentiation CD 36, the main fatty acid transporter in cardiomyocytes.
Paired with high levels of circulating FFAs, increased abundance of CD36 on the sarcolemmal membrane raises intracellular fatty acid availability and turnover Figure 2. Metabolic inflammation promotes myocardial remodeling.
High levels of circulating inflammatory cytokines and metabolic substrates activate inflammatory cascades in different cardiac cell types linked to cellular dysfunction. Endothelial activation facilitates leucocyte adhesion and transmigration into the myocardium thereby aggravating the low-grade inflammatory state.
Both free fatty acids FFAs and high glucose levels modulate the polarization of monocyte-derived macrophages MDM which secrete inflammatory and profibrotic cytokines.
Cardiac insulin resistance is promoted by inflammatory cytokines, including tumor necrosis factor alpha TNF-αand goes along with down-regulation of the insulin-dependent glucose transporter 4 GLUT4 and upregulation of the fatty acid transporter cluster of differentiation CD 36 thus contributing to lipotoxicity, mitochondrial dysfunction and accumulation of reactive oxygen species ROS.
In addition, direct effects of circulating inflammatory mediators lead to endothelial ROS formation and microvascular dysfunction. FFA overload leads to mitochondrial dysfunction and uncoupling of fatty acid oxidation from ADP phosphorylation in cardiomyocytes As a result of deranged cardiac lipid metabolism, cardiac triacylglycerols and toxic intermediate products such as diacylglycerols and ceramides are formed 17 and accumulate in the heart of obese and diabetic patients 76 — Cardiac lipotoxicity has been implicated in the generation of reactive oxygen species ROScell apoptosis, defective insulin signaling, and impaired calcium handling 79 — While the exact mechanisms underlying cardiac lipotoxicity remain elusive and are subject of ongoing investigations, the combination of myocardial inflammation, insulin resistance and excess supply of FFA emerges as a decisive factor Nutrient overload activates different inflammatory signaling cascades in cardiomyocytes which contribute to cell hypertrophy, apoptosis, and mechanical dysfunction The regulation of inflammatory programs in cardiomyocytes is closely linked to intracellular ROS accumulation resulting from deranged cardiac substrate utilization in diabetes and obesity 17 Excess availability of lipids and glucose favors the production of ROS 1784 which in turn enhances the transcription and functional activity of NF-κB 85 — Cardiomyocyte-specific inhibition of NF-kB signaling through overexpression of inhibitor of NF-κB IκB -α mitigates cardiac alterations in hyperglycemic mice—highlighting the importance of this axis In addition, high glucose concentrations directly activate a number of pro-inflammatory pathways in cardiomyocytes converging toward NF-κB.
Exposure to high glucose levels enhances the expression of high-mobility group box 1 HMGB1 protein in cardiomyocytes thereby activating mitogen-activated protein kinase MAPK and NF-κB which leads to TNF-α and IL-6 secretion High glucose also induces upregulation of TNF-α, IL-1β, IL-6, and IL through activation of JNK and NF-κB Another mechanism linking glucose metabolism to inflammation is histone 3 lysine 9 trimethylation H3K9me3 at the IL-6 promoter under high glucose conditions favoring its upregulation Moreover, posttranslational modification of the NF-κB p65 subunit by O-linked N-acetylglucosamine O-GlcNAc enhancing its transcriptional activity under hyperglycemic conditions may also apply to cardiomyocytes Likewise, hyperglycemia-induced epigenetic changes that increase p65 expression may be of relevance in cardiomyocytes 3844 Excess availability of FFAs contributes to deranged substrate utilization of the heart in high metabolic states leading to lipotoxicity and ROS formation Exposure of human cardiomyocytes to saturated fatty acids enhances NF-κB binding activity and raises nuclear p65 protein levels leading to enhanced expression of TNF-α, IL-6, and CCL-2 Similar findings were reported in hearts from mice fed a high-fat diet Direct activation of the NOD- LRR- and pyrin domain-containing protein NLRP 3 inflammasome by accumulating ceramides has been demonstrated in other cell types including adipocytes and may also be of importance in cardiomyocytes.
Endothelial cells are a central component of the cardiac vasculature forming a barrier between blood and myocardial tissue. Aside from their regulatory function in substrate exchange, endothelial cells control myocardial blood flow, and immune cell recruitment 95 —
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Cell Host Microbe 22 , — Marchesi, J. The gut microbiota and host health: a new clinical frontier. Download references. The authors thank members of the Tilg and Elinav laboratories for discussions and apologize to authors whose work was not included due to space constraints. is supported by the Excellence Initiative Competence Centres for Excellent Technologies — COMET of the Austrian Research Promotion Agency FFG: Research Centre of Excellence in Vascular Ageing Tyrol, VASCage K-Project No. is supported by a Gilead Biosciences Fellowship. is supported by Y. and R. Ungar, the Abisch Frenkel Foundation for the Promotion of Life Sciences, the Gurwin Family Fund for Scientific Research, the Leona M. and Harry B. Helmsley Charitable Trust, the Crown Endowment Fund for Immunological Research, the estate of J. Gitlitz, the estate of L. Hershkovich, the Benoziyo Endowment Fund for the Advancement of Science, the Adelis Foundation, J. and V. Schwartz, A. and G. Markovitz, A. and C. Adelson, the French National Centre for Scientific Research CNRS , D. Schwarz, the V. Schwartz Research Fellow Chair, L. Steinberg, J. Halpern, A. Edelheit, grants funded by the European Research Council, a Marie Curie Integration grant, the German—Israeli Foundation for Scientific Research and Development, the Israel Science Foundation, the Minerva Foundation, the Rising Tide Foundation, the Helmholtz Foundation, and the European Foundation for the Study of Diabetes. is a senior fellow of the Canadian Institute of Advanced Research CIFAR and an international scholar of the Bill and Melinda Gates Foundation and Howard Hughes Medical Institute HHMI. Immunology Department, Weizmann Institute of Science, Rehovot, Israel. Digestive Centre, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel. |
| Metabolism, Inflammation, & How They Interact | Buy or subscribe. Subjects Metabolic Metabolism and inflammation Microbiome Mucosal immunology. Upadhyay, V. Citation: Wenzl FA, Inflammatikn S, Mohammed SA, Carbohydrate metabolism in liver S, Metabolixm TF, Costantino S and Paneni F Inflammation in Metabolic Cardiomyopathy. In this study, the authors identify phenylacetic acid, a microbial product, as a trigger of hepatic steatosis, providing further evidence for a role of the gut microbiota in this process. |
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Selected publications Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes. Pillon NJ, Smith JAB, Alm PS, Chibalin AV, Alhusen J, Arner E, Carninci P, Fritz T, Otten J, Olsson T, van Doorslaer de Ten Ryen S, Deldicque L, Caidahl K, Wallberg-Henriksson H, Krook A, Zierath JR Sci Adv 09;8 36 :eabo Metabolic Consequences of Obesity and Type 2 Diabetes: Balancing Genes and Environment for Personalized Care. och Edla Johanssons vetenskapliga stiftelse Sigurd och Elsa Goljes Foundation Lars Hiertas Minne Foundation Magnus Bergvalls Foundation Group members. Nicolas Pillon Team leader. E-post: nicolas. pillon ki. Alesandra Marica Research assistant. E-post: alesandra. Ahmed Abdelmoez PhD student. E-post: ahmed. Sci Rep 7 : de Souza CJ , Eckhardt M , Gagen K , Dong M , Chen W , Laurent D , Burkey BF. Effects of pioglitazone on adipose tissue remodeling within the setting of obesity and insulin resistance. 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| The intestinal microbiota fuelling metabolic inflammation | Nature Reviews Immunology | For example, direct and paracrine signals from M1 classically activated macrophages can impair insulin signaling and adipogenesis in adipocytes, while unstimulated or M2 alternatively activated macrophages fail to generate these effects Similar effects on adipocyte inflammation and glucose transport are generated by signals from activated conventional T cells such as IFN-γ In parallel, dysregulated macrophage-myocyte and macrophage-hepatocyte signaling can influence insulin sensitivity 14 , While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity. Cellular mediators of inflammation and immunity in obesity. The multisystem effects of obesity are linked to an imbalance in homeostatic and proinflammatory immune responses. Obesity triggers inflammatory pathways in the brain and adipose tissue that dysregulate physiological responses that maintain insulin and leptin sensitivity. Over time, ectopic lipid accumulation in muscle, liver, and blood vessels activates tissue leukocytes, contributes to organ-specific disease, and exacerbates systemic insulin resistance. Cellular- and cytokine-mediated inflammation in pancreatic islets accelerates the progression toward diabetes. Immunity and the maintenance of metabolic homeostasis. In some cases, adaptive immune responses may be beneficial and help preserve metabolic homeostasis. All metabolic tissues contain resident populations of leukocytes present even in lean healthy animals, indicating that the immune system is poised to respond to nutrient-derived signals 16 , For example, the extent of adipose tissue macrophage ATM infiltration is dynamically altered with lipid flux in adipocytes in lean and obese states, and may serve to suppress lipolytic signals 4. ATMs are recruited to adipose tissue when chemokine or lipid release lipolysis is triggered and may function to promote lipid storage by suppressing lipolysis. These events could be classified as an inflammatory response, as it involves the acute recruitment of leukocytes to fat, but it lacks many of the cardinal signs of classic inflammation dolor, rubor, calor, and tumor. Reconciling these observations requires a more expansive view of what immunologic activation means beyond the classical proinflammatory paradigm. The diversity of ATM function supports this broad view, as does the observation that leukocytes adopt a wide range of activation states dependent upon the local stimuli Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state M1 that generates bactericidal or Th1 responses typically associated with obesity. In contrast, Th2 cytokines such as IL-4 and IL generate an alternative macrophage activation state M2 that promotes fibrotic responses and attenuation of classical NF-κB—dependent activation pathways. The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ, well-known regulators of lipid metabolism and mitochondrial activity Ppard - and Pparg -knockout mice fail to generate an M2 activation state and are more susceptible to the M1-skewed inflammation that accompanies diet-induced obesity DIO in the liver and adipose tissue 17 , 25 , Physiologic enhancement of the M2 pathways e. In fat, the M2 state of resident ATMs is maintained by cytokine production e. This demonstrates that maintaining metabolic homeostasis requires a balanced immune response and an integrated network of multiple cell types. Likewise, there appear to be innate systems by which nutrient signals are utilized to self-limit inflammation. For example, the obesity-induced increase in expression of GPR, an omega-3 fatty acid FA receptor on macrophages capable of attenuating M1 macrophage activation and increasing M2 gene expression, limits inflammation; it is possible that this mechanism might be exploited in future drug development The discovery of ATM activation with obesity sparked a wave of interest into how immune responses intersect with obesity 31 , We know now that the dynamic regulation of inflammatory cells with obesity is not limited to fat and that inflammatory and metabolic signals converge in a myriad of contexts. This provides new opportunities to understand the pathogenesis of many organ-specific diseases associated with obesity Figure 1. Pancreatic islets. Relevant to type 2 diabetes is the demonstration that inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes 33 , The mediators of these effects are multifactorial and likely involve cytokines produced by β cells themselves As in adipose tissue, macrophages accumulate in islets with DIO and may be a significant source of proinflammatory cytokines that block β cell function This point is often ignored in studies that manipulate macrophages by Cre-mediated recombination or BM transplantation and may be an underappreciated mechanism for protection from diabetes in many animal models. Adipose tissue. Adipose tissue insulin resistance and dysfunctional lipid storage in adipocytes are sentinel events in the progression toward metabolic dysregulation with obesity. Forced expansion of adipose tissue by transgenic overexpression of the adipokine adiponectin prevents metabolic disease despite massive obesity Since an estimated excess of 20—30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass Inputs into this inflammatory response include ER stress, adipose tissue hypoxia, and adipocyte death 41 — NK cells, NKT cells, and mast cells are also implicated in metainflammation 40 , 45 , Overall, our challenge in understanding adipose tissue inflammation will be to identify the temporal and spatial interactions between leukocytes in fat in the context of inflammatory initiation as well as their resolution. Inflammation in liver and muscle. Nonalcoholic fatty liver disease NAFLD is a strong risk factor for insulin resistance, nonalcoholic steatohepatitis, and dyslipidemia, independent of visceral adiposity Many of the signaling pathways involved in both inflammation and metabolism are elevated in steatotic liver e. In addition, modulation of PPARδ-dependent M2 polarization pathways protects mice from NAFLD 17 , These effects may be mediated via Kupffer cells resident in the liver, or by unique cell populations recruited to the liver with obesity There is also evidence of increased inflammatory cytokine production and increased inflammation in skeletal muscle in obesity Myocytes have the capacity to respond to inflammatory signals via pattern recognition receptors PRRs such as TLR4 with direct metabolic effects Muscle inflammation may be linked to infiltrating macrophages that are induced in obese muscle and have properties of M1 activation 23 , This topic is complicated by the fact that leukocyte trafficking of monocytes and macrophages is intrinsically linked to muscle injury and repair 55 , increasing the challenge of de-convoluting the acute and chronic inflammatory changes in muscle with DIO. Hypothalamic inflammation and obesity. Human genome wide association studies have identified loci near or within numerous neuronal genes that affect BMI, suggesting that variation in the central control of metabolism plays a prominent role in genetic obesity risk Lipid infusion and a high-fat diet HFD activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage With DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS 58 , Part of this effect is mediated by saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling The effects of brain inflammation on the metabolic function of peripheral tissues are broad. Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension 63 — Many of these effects are generated by signals from the sympathetic nervous system, which is also capable of inducing inflammatory changes in adipose tissue in response to neuronal injury A future challenge is to understand how inflammatory signals in the brain generate responses that in some cases generate negative energy balance anorexia , while in other cases generates positive energy balance weight gain The dynamic interplay between hypothalamic inflammation and obesity suggest additional targets for antiinflammatory therapies in obesity. A key extension of these observations is the potential that antiinflammatory pathways may counteract these CNS inflammatory events and improve leptin sensitivity. Another intriguing possible link between inflammation and the risk for obesity involves events in early embryonic development. 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A metabolic shift toward pentose phosphate pathway is necessary for amyloid fibril- and phorbol myristate acetate-induced neutrophil extracellular trap NET formation. |
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