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Obesity, Inflammation, and Insulin Resistance

2007; Elsevier BV; Volume: 132; Issue: 6 Linguagem: Inglês

10.1053/j.gastro.2007.03.059

1528-0012

Steven E. Shoelson, Laura Herrero, Afia Naaz,

Adipose Tissue and Metabolism

Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Weight gain and obesity are major risk factors for conditions and diseases ranging from insulin resistance and type 2 diabetes mellitus to atherosclerosis and the sequelae of nonalcoholic fatty liver disease. A chronic, subacute state of inflammation often accompanies the accumulation of excess lipid in adipose tissue and liver (hepatic steatosis), evidenced by changes in both inflammatory cells and biochemical markers of inflammation. These changes can be seen in the involved tissues and systemically, in terms of elevated circulating levels of inflammatory markers. The link between obesity and inflammation has therefore raised the important question of whether obesity-induced inflammation plays a pathogenic role in the development and progression of these disorders. We review the rapidly expanding body of animal and clinical data that support potential roles for inflammation in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Mammals have evolved mechanisms to store energy during periods of plenty, which helps to guarantee survival during periods of drought and famine. Excess nutrient is stored as triglyceride, primarily in the adipose tissue but in other tissues as well. In addition to the beneficial effects of nutrient storage, however, the long-term storage of excessive amounts of lipid can have a negative impact on health, especially under conditions of longer life span and decreased physical activity. The adverse health consequences of weight gain and obesity are especially prominent following prolonged periods of positive energy balance and may be most pronounced when foods are energy dense because of high proportions of simple carbohydrates and saturated fats, such as occurs today in developed Western societies. As a consequence of sustained overnutrition, obesity has become epidemic in industrialized countries and is increasingly common in developing countries worldwide. The prevalence rates are continuing to rise, most rapidly in developing countries, and obesity is occurring in all groups at younger ages. The World Health Organization estimates that globally there are >1 billion overweight adults, 300 million of whom are obese.1World Health Organization. Fact sheet: obesity and overweight. Available at: http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed February 8, 2007.Google Scholar Since 1980, obesity rates have risen more than 3-fold in some areas of North America, the United Kingdom, Eastern Europe, the Middle East, the Pacific Islands, Australasia, and China. Very worrisome are the concurrent and parallel increases in the prevalence of pathologic conditions associated with obesity, which include type 2 diabetes mellitus (T2D), cardiovascular disease (CVD), hypertension, hypercholesterolemia, hypertriglyceridemia, nonalcoholic fatty liver disease (NAFLD), arthritis, asthma, and certain forms of cancer. We review the growing evidence that supports the hypothesis that a subacute state of chronic inflammation associated with obesity provides a molecular link to some of these pathologic conditions. In addition to containing adipocytes, adipose tissue is well vascularized and innervated and contains a connective tissue matrix and numerous immune cells including macrophages.2Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr, A.W. Obesity is associated with macrophage accumulation in adipose tissue.J Clin Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (0) Google Scholar, 3Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (0) Google Scholar White adipose tissue (WAT) is most familiar as the type of fat in which triglyceride is stored and from which lipids are mobilized for systemic utilization when other tissues require energy. WAT is often subdivided into subcutaneous and abdominal depots, whose physiologies may be distinguished and whose roles in pathology may also be distinct. This is contrasted with brown adipose tissue, whose main function is thought to be nonshivering thermogenesis, a process of heat production through the uncoupling of oxidative phosphorylation. Uncoupling protein-1, an integral membrane protein located in the mitochondrial inner membrane, regulates the thermogenic proton leak in brown adipose tissue.4Krauss S. Zhang C.Y. Lowell B.B. The mitochondrial uncoupling-protein homologues.Nat Rev Mol Cell Biol. 2005; 6: 248-261Crossref PubMed Scopus (268) Google Scholar Originally considered to be a passive depot for energy storage, WAT is now known to secrete a variety of substances that help to regulate metabolic homeostasis. These include leptin, adiponectin, resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1; also known as CCL2), plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, visfatin, retinol-binding protein-4, serum amyloid A (SAA), and others.5Fried S.K. Bunkin D.A. Greenberg A.S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.J Clin Endocrinol Metab. 1998; 83: 847-850Crossref PubMed Scopus (872) Google Scholar, 6Fukuhara A. Matsuda M. Nishizawa M. Segawa K. Tanaka M. Kishimoto K. Matsuki Y. Murakami M. Ichisaka T. Murakami H. Watanabe E. Takagi T. Akiyoshi M. Ohtsubo T. Kihara S. Yamashita S. Makishima M. Funahashi T. Yamanaka S. Hiramatsu R. Matsuzawa Y. Shimomura I. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.Science. 2005; 307: 426-430Crossref PubMed Scopus (895) Google Scholar, 7Shimomura I. Funahashi T. Takahashi M. Maeda K. Kotani K. Nakamura T. Yamashita S. Miura M. Fukuda Y. Takemura K. Tokunaga K. Matsuzawa Y. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.Nat Med. 1996; 2: 800-803Crossref PubMed Scopus (615) Google Scholar, 8Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. The hormone resistin links obesity to diabetes.Nature. 2001; 409: 307-312Crossref PubMed Scopus (2447) Google Scholar Leptin and adiponectin are considered to be primary adipocytokines because they appear to be produced primarily by adipocytes. Resistin, however, is produced in humans by mononuclear cells such as macrophages and by both adipocytes and macrophages in rodents.8Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. The hormone resistin links obesity to diabetes.Nature. 2001; 409: 307-312Crossref PubMed Scopus (2447) Google Scholar, 9Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Crossref PubMed Scopus (877) Google Scholar TNF-α, IL-6, MCP-1, visfatin, and PAI-1 are expressed in adipocytes as well as activated macrophages and/or other immune cells. The relative amounts of each produced by the adipocyte versus the macrophages present in the adipose tissue are still unclear. The potential roles of leptin, adiponectin, resistin, and visfatin as mediators linking adipose tissue, inflammation, and immunity has been recently reviewed.9Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Crossref PubMed Scopus (877) Google Scholar Thus, adipose tissue is a complex and active secretory organ that both sends and receives signals that modulate energy expenditure, appetite, insulin sensitivity, endocrine and reproductive functions, bone metabolism, inflammation, and immunity. Immune cells in the adipose tissue, specifically macrophages, have increasingly caught the attention of the scientific community. In both humans and mice, the number of bone marrow-derived macrophages correlates with obesity and adipocyte size.2Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr, A.W. Obesity is associated with macrophage accumulation in adipose tissue.J Clin Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (0) Google Scholar Adipose tissue in obese subjects is characterized by macrophage infiltration,2Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr, A.W. Obesity is associated with macrophage accumulation in adipose tissue.J Clin Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (0) Google Scholar, 3Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (0) Google Scholar which has been shown to be stimulated by adipocyte production of the monocyte chemoattractant MCP-1.10Kanda H. Tateya S. Tamori Y. Kotani K. Hiasa K. Kitazawa R. Kitazawa S. Miyachi H. Maeda S. Egashira K. Kasuga M. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.J Clin Invest. 2006; 116: 1494-1505Crossref PubMed Scopus (665) Google Scholar Moreover, adipose tissue-resident macrophages are also a source of proinflammatory factors that may modulate the secretory activity of adipocytes.3Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (0) Google Scholar Both adipocytes and macrophages contribute to WAT-derived IL-6. Abdominal WAT produces higher levels of IL-6 than subcutaneous WAT.5Fried S.K. Bunkin D.A. Greenberg A.S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.J Clin Endocrinol Metab. 1998; 83: 847-850Crossref PubMed Scopus (872) Google Scholar, 11Fain J.N. Madan A.K. Hiler M.L. Cheema P. Bahouth S.W. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans.Endocrinology. 2004; 145: 2273-2282Crossref PubMed Scopus (641) Google Scholar In fact, there are several ways that subcutaneous visceral adipose tissue depots differ, including by cell size,12Johnson P.R. Hirsch J. Cellularity of adipose depots in six strains of genetically obese mice.J Lipid Res. 1972; 13: 2-11Abstract Full Text PDF PubMed Google Scholar, 13Krotkiewski M. Bjorntorp P. Sjostrom L. Smith U. Impact of obesity on metabolism in men and women Importance of regional adipose tissue distribution.J Clin Invest. 1983; 72: 1150-1162Crossref PubMed Google Scholar metabolic activity, and potential role in insulin resistance.14Coon P.J. Rogus E.M. Drinkwater D. Muller D.C. Goldberg A.P. Role of body fat distribution in the decline in insulin sensitivity and glucose tolerance with age.J Clin Endocrinol Metab. 1992; 75: 1125-1132Crossref PubMed Scopus (114) Google Scholar, 15Gastaldelli A. Miyazaki Y. Pettiti M. Matsuda M. Mahankali S. Santini E. DeFronzo R.A. Ferrannini E. Metabolic effects of visceral fat accumulation in type 2 diabetes.J Clin Endocrinol Metab. 2002; 87: 5098-5103Crossref PubMed Scopus (100) Google Scholar Visceral adiposity, rather than simply a high body mass index (BMI), correlates best with increased risk of CVD and diabetes, although the biochemical and physiologic reasons for this are still unclear. One possible explanation is that visceral but not subcutaneous WAT has direct access to the portal circulation so that substances produced by visceral fat may directly impact the liver. The specialized anatomy of the liver provides a mechanism for the portal and arterial circulations to interact with both liver parenchyma (hepatocytes) and the many immune cells also located within the liver. The hepatocytes represent approximately two thirds of the total cells in liver. The remaining cells are diverse and include biliary epithelial cells, sinusoidal endothelial cells, Kupffer cells (resident macrophages), stellate cells (also called Ito or fat-storage cells), dendritic cells, and several types of lymphocytes16Racanelli V. Rehermann B. The liver as an immunological organ.Hepatology. 2006; 43: S54-S62Crossref PubMed Scopus (237) Google Scholar (Figure 1). Blood from the gastrointestinal tract travels via the afferent portal vein to the hepatic sinusoids in which it interacts with the sinusoidal endothelial cells and hepatic immune cells on its way to the efferent central veins. The sinusoidal endothelial cells represent approximately 50% of the nonparenchymal cells. Unlike endothelial cells in many organs, the sinusoidal endothelial cells form a sieve-like, fenestrated epithelium and participate in antigen presentation. The Kupffer cells and lymphocytes account for the bulk of immune cells in liver. Kupffer cells occupy the sinusoidal space where they phagocytose microorganisms and other debris. The lymphocytes are largely T cells and natural killer (NK) cells, with B cells making up a much smaller percentage. NKT cells account for up to 30% of the total lymphocytes in liver, which is a higher percentage than is typically found in other organs. The accumulation of lipid in the liver often accompanies and parallels weight gain and obesity. Hepatic steatosis, the accumulation of lipid in the hepatocytes, has negative effects on liver function, which may also be mediated by inflammation. For example, messenger RNA (mRNA) expression of proinflammatory cytokines including IL-6, TNF-α, and IL-1β increases in liver with increasing adiposity.17Cai D. Yuan M. Frantz D.F. Melendez P.A. Hansen L. Lee J. Shoelson S.E. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.Nat Med. 2005; 11: 183-190Crossref PubMed Scopus (792) Google Scholar This suggests that steatosis might induce a subacute inflammatory response in liver similar to that seen with the accumulation of lipid into the adipocytes. As an additional or alternative possibility, proinflammatory cytokines and lipids and other substances produced in the abdominal fat and carried to the liver through the portal circulation could contribute to hepatic inflammation. Proinflammatory substances activate the Kupffer cells, which are abundant in the liver and account for over 5% of total cells. The activation state of Kupffer cells but not their number increases with obesity.17Cai D. Yuan M. Frantz D.F. Melendez P.A. Hansen L. Lee J. Shoelson S.E. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB.Nat Med. 2005; 11: 183-190Crossref PubMed Scopus (792) Google Scholar The many additional immune cell types in liver may also play roles in inflammation-induced insulin resistance. For example, the number of NKT cells is selectively reduced in the steatotic livers of obese, leptin-deficient ob/ob mice or high-fat diet (HFD)-treated mice.18Guebre-Xabier M. Yang S. Lin H.Z. Schwenk R. Krzych U. Diehl A.M. Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage.Hepatology. 2000; 31: 633-640Crossref PubMed Google Scholar, 19Li Z. Soloski M.J. Diehl A.M. Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.Hepatology. 2005; 42: 880-885Crossref PubMed Scopus (130) Google Scholar Given that NKT cells have regulatory roles in immune function,20Godfrey D.I. Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells.J Clin Invest. 2004; 114: 1379-1388Crossref PubMed Scopus (0) Google Scholar such significant changes in number could have substantial ramifications in terms of both physiology and pathology. Interestingly, adoptive transfer of NKT cells into ob/ob mice resulted in a reduction of the hepatic fat content, steatosis, and improvement in glucose intolerance.21Elinav E. Pappo O. Sklair-Levy M. Margalit M. Shibolet O. Gomori M. Alper R. Thalenfeld B. Engelhardt D. Rabbani E. Ilan Y. Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping.J Pathol. 2006; 209: 121-128Crossref PubMed Scopus (52) Google Scholar Epidemiologic evidence for links between obesity and inflammation have existed for decades, although these findings were not appreciated in terms of the pathophysiologic conditions associated with obesity. For example, the levels of circulating fibrinogen and other acute phase reactants were found to be elevated in obesity.22Fearnley G.R. Vincent C.T. Chakrabarti R. Reduction of blood fibrinolytic activity in diabetes mellitus by insulin.Lancet. 1959; 2: 1067Abstract PubMed Google Scholar, 23Grace C.S. Goldrick R.B. 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Ferrante Jr, A.W. CCR2 modulates inflammatory and metabolic effects of high-fat feeding.J Clin Invest. 2006; 116: 115-124Crossref PubMed Scopus (545) Google Scholar The inflammatory signal is enhanced by the cross talk among endothelial cells, adipocytes, and resident macrophages, which together contribute to the production of proinflammatory cytokines and induce a state of local and systemic insulin resistance. This is consistent with reports of increased expression of proinflammatory genes by macrophages in the adipose tissue of obese mice followed by exaggerated increases in circulating insulin.3Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. Sole J. Nichols A. Ross J.S. Tartaglia L.A. Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (0) Google Scholar It is thus possible that the accumulation of lipids in adipocytes initiates the inflammatory signal in adipose tissue and that resident macrophages serve to amplify the signal.Figure 3Potential mechanisms for obesity-induced inflammation. The accumulation of lipids in adipose tissue and the expansion of the fat mass lead to the initiation of an inflammatory process. This may be initiated through the production of proinflammatory cytokines and chemokines by the adipocytes, including TNF-α, IL-6, leptin, resistin, MCP-1, and PAI-1. Endothelial cells respond through the increased expression of adhesion molecules, which along with the chemokines serve to recruit immune cells including monocyte-derived macrophages to the adipose tissue. Together, the adipocyte-, immune cell-, and endothelial cell-derived substances create an inflammatory milieu that promotes insulin resistance locally. Similar proinflammatory and proatherogenic mediators enter the circulation to promote insulin resistance and increase risk for atherosclerosis.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Two transcription factor-signaling pathways have been linked to the proinflammatory effects of obesity and insulin resistance: the NF-κB pathway, which is activated by inhibitor of NF-κB (IκB) kinase β (IKKβ), and the c-Jun NH2-terminal kinase (JNK) pathway. These pathways are activated by many of the same proinflammatory stimuli including cytokines such as TNF-α, which in addition to being activators of NF-κB are also NF-κB-regulated products. Both pathways are also activated by pattern recognition receptors, such as the receptor for advanced glycation end products and the toll-like receptors, which are gatekeepers of the innate immune system. In addition to being activated by bacterial, viral, and fungal products, toll-like receptors can be activated by fatty acids,40Lee J.Y. Sohn K.H. Rhee S.H. Hwang D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.J Biol Chem. 2001; 276: 16683-16689Crossref PubMed Scopus (414) Google Scholar, 41Shi H. Kokoeva M.V. Inouye K. Tzameli I. Yin H. Flier J.S. TLR4 links innate immunity and fatty acid-induced insulin resistance.J Clin Invest. 2006; 116: 3015-3025Crossref PubMed Scopus (934) Google Scholar which suggests a potential link between elevated circulating or tissue lipid concentrations and the immune system. Reactive oxygen species, endoplasmic reticulum stress, and ceramides are increased by adiposity, and all have also been shown to activate both JNK and NF-κB.42Furukawa S. Fujita T. Shimabukuro M. Iwaki M. Yamada Y. Nakajima Y. Nakayama O. Makishima M. Matsuda M. Shimomura I. Increased oxidative stress in obesity and its impact on metabolic syndrome.J Clin Invest. 2004; 114: 1752-1761Crossref PubMed Google Scholar, 43Ozcan U. Cao Q. Yilmaz E. Lee A.H. Iwakoshi N.N. Ozdelen E. Tuncman G. Gorgun C. Glimcher L.H. Hotamisligil G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.Science. 2004; 306: 457-461Crossref PubMed Scopus (1177) Google Scholar, 44Summers S.A. Ceramides in insulin resistance and lipotoxicity.Prog Lipid Res. 2006; 45: 42-72Crossref PubMed Scopus (269) Google Scholar In addition, FFA increase the activities of various protein kinase C isoforms, which can in turn activate IKK and JNK.45Gao Z. Zhang X. Zuberi A. Hwang D. Quon M.J. Lefevre M. Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes.Mol Endocrinol. 2004; 18: 2024-2034Crossref PubMed Scopus (163) Google Scholar More information about the molecular links between inflammation and insulin resistance can be found in recently published reviews.9Tilg H. Moschen A.R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity.Nat Rev Immunol. 2006; 6: 772-783Crossref PubMed Scopus (877) Google Scholar, 46Hotamisligil G.S. Inflammation and metabolic disorders.Nature. 2006; 444: 860-867Crossref PubMed Scopus (1860) Google Scholar, 47Shoelson S.E. Lee J. Goldfine A.B. Inflammation and insulin resistance.J Clin Invest. 2006; 116: 1793-1801Crossref PubMed Scopus (1) Google Scholar Consistent with the findings described above, genetic disruption of NF-κB and JNK signaling pathways has been shown to improve insulin resistance. Heterozygous IKKβ+/− mice, fed with an HFD or crossed with obese ob/ob mice, were protected against the development of insulin resistance.48Yuan M. Konstantopoulos N. Lee J. Hansen L. Li Z.W. Karin M. Shoelson S.E. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ.Science. 2001; 293: 1673-1677Crossref PubMed Scopus (967) Google Scholar Moreover, inhibition of NF-κB in macrophages or liver, through the tissue-specific expression of dominant inhibitory IκBα or tissue-specific deletion of IKKβ, attenuates inflammatory gene expression and insulin resistance in response to HFD (Table 1).17Cai D. Yuan M. Frantz D.F. Melendez P.A. Hansen L. Lee J. Shoelson S.E. Local and s