Resistin- and Obesity-Associated Metabolic Diseases

710 Review Resistin- and Obesity-associated Metabolic Diseases Author M . A . L a z a r Affi liation Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, USA Key words Abstract regulator of glucose metabolism and insulin sensi- ᭹ ᭤ obesity & tivity. In humans, resistin is derived made mainly ᭹ ᭤ insulin resistance The link between obesity and diabetes is strong from macrophages. Given the emerging interre- ᭹᭤ resistin as well as complex. Fat cells produce many circu- lationship between infl ammation and metabolic ᭹ ᭤ adipokine lating regulators of insulin sensitivity, including disease, hyperresistinemia may be a biomarker, pro-infl ammatory cytokines. In rodents, resistin and/or a mediator, of metabolic and infl amma- is produced by adipose tissue, and is a signifi cant tory diseases in humans as well as in rodents . The problem of obesity-associated radic cases, insulin receptor (IR), glucose trans- metabolic diseases porters, and insulin receptor substrates (IRS) are & normal [7] . Obesity is strongly associated with Diabetes mellitus (DM) is a chronic disease char- insulin resistance and type 2 DM in humans as acterized by hyperglycemia and other metabolic well as rodent models and, although the connec- abnormalities. The natural history of DM includes tion between increased adiposity and insulin numerous complications including heart disease, resistance remains a mystery, two critical con- stroke, kidney failure, blindness, and neuropathy cepts have emerged over the past decade. The [1] . Aggressive treatment of hyperglycemia fi rst is that increased adipose tissue is indeed reduces these risks [2] . A minority of patients linked to the insulin resistance in key insulin- suffer from type 1 DM, caused by pancreatic - sensitive tissues such as liver and muscle [8] . The cell failure leading to an absolute loss of insulin. second is that adipose tissue, where the majority received 16.10.2006 Type 2 DM stems from failure of the body to of energy equivalents are stored in the body in accepted 01.02.2007 respond normally to insulin – called “ insulin the form of triglycerides (TG), is an endocrine Bibliography resistance ” – coupled with the inability to pro- organ that communicates with other tissues via a DOI 10.1055/s-2007-985897 duce enough insulin to overcome this resistant host of secreted factors [9, 10] . Horm Metab Res 2007; state. This common form of diabetes is often 39: 710 – 716 associated with obesity, and the current epidem- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. © Georg Thieme Verlag KG ics of these two conditions are seemingly related Adipose tissue as an endocrine organ Stuttgart · New York [3] . This is glaringly evident in children, who are & ISSN 0018-5043 increasingly plagued by obesity, and in whom Adipose tissue has long been known to secrete the prevalence of type 2 DM (formerly termed free fatty acids (FFA), the product of TG hydroly- Correspondence M. A. Lazar “ adult onset ” ) is approaching that of type 1 dia- sis, in response to the body ’ s demand for energy Division of Endocrinology betes (formerly termed “ juvenile onset” ) [4] . The in times of reduced nutrient supply. It is now rec- Diabetes and Metabolism epidemic of diabetes has a huge associated cost ognized that increased serum levels of FFA is an Department of Medicine and in terms of healthcare dollars as well as human important factor contributing to insulin resist- The Institute for Diabetes morbidity and mortality [5] . Recent studies pre- ance in peripheral tissues [11] . In addition, adi- Obesity and Metabolism dict that one in three Americans born in the year pocytes also secrete a variety of polypeptides University of Pennsylvania 2000 will develop diabetes in their lifetime [6] ; including leptin, adipsin, adiponectin, resistin, School of Medicine 19104-6149 Philadelphia the vast majority of cases will be obesity-associ- tumor necrosis factor- (TNF ), interleukin-6 (IL- USA ated type 2 DM. 6), plasminogen activator inhibitor-1 (PAI-1), and Tel.: + 1 / 215 / 898 01 98 The mechanism underlying insulin resistance in monocyte chemoattractant protein-1 (MCP-1) Fax: + 2 / 215 / 898 54 08 type 2 DM is not well understood. Except for spo- [12] . A subset of these adipose-derived proteins [email protected] Lazar MA. Resistin and Metabolic Diseases … Horm Metab Res 2007; 39: 710 – 716 Review 711 is adipocyte-specifi c, while others are not. In rodents, the adi- innate immune response, for example by bacterial endotoxin pocyte-specifi c proteins leptin, adiponectin, and resistin have all during sepsis [33] , results in insulin resistance that contributes been implicated in the modulation of insulin sensitivity. Leptin to the high mortality of critical illness [34] . The interaction is an insulin-sensitizing hormone, and defi ciency due to leptin between infl ammation and insulin signaling is also suggested by gene mutation [13] or reduced adipose mass causes insulin the ability of aspirin to improve insulin resistance, in part by resistance [14, 15] . In obese states other than that due to leptin preventing the antagonistic effects of fatty acids and cytokines gene mutation, however, leptin levels are markedly increased [35] . Perhaps the response to infection is more effective when but leptin action is reduced by concomitant leptin resistance glucose is shunted from muscle to the infl ammatory cells [16] . Another adipose-specifi c hormone, adiponectin, has insu- involved in the immune response and tissue repair [36] . lin-sensitizing properties, but its levels are decreased in obesity, thereby contributing to insulin resistance [17] . Resistin, which in rodents is an adipocyte-specifi c circulating hormone whose Peroxisome Proliferator Activated Receptor increased levels in obesity promote insulin resistance [18] , is the (PPAR ) and insulin sensitivity subject of this review and will be discussed at great length later & in this section. PPAR , a member of the nuclear hormone receptor superfamily Intriguingly, quite a few adipose-secreted proteins that are also of ligand-regulated transcription factors, is the molecular tar- secreted by other tissues also play a role in innate immunity, a get of the thiazolidinedione (TZD) class of antidiabetic drugs relatively primitive defense mechanism against infection [19] . that improve insulin sensitivity throughout the body [37] . Proteins such as tumor necrosis factor- and interleukin-6 are PPAR expression in adipose tissue is 10 – 100-fold greater than cytokines that are mainly produced by macrophages. These in muscle and liver [38, 39] and mice lacking adipose tissue fail cytokines directly promote infl ammation, and also act on the to respond to TZD treatment [40, 41] whereas mice lacking liver to produce acute phase proteins that contribute to the PPAR in skeletal muscle retain normal responsivity to TZDs infl ammatory process, and are also produced by adipocytes. A [42] . These observations strongly suggest that the antidiabetic number of these cytokines induce Suppressor of Cytokine Sign- actions of TZDs are mediated by changes in adipose-secreted aling-3 (SOCS-3), an intracellular signaling molecule that impairs products; our laboratory and others have hypothesized that the the signaling of both leptin and insulin. SOCS-3 levels are ele- adipocyte-secreted factors altered by TZD treatment are likely vated in obesity and may thus represent a fi nal common path- to play a role in the pathophysiology of obesity-associated insu- way of obesity-associated resistance to the actions of both leptin lin resistance and diabetes [43] . Indeed, TZDs lower plasma FFA and insulin [20] . They may also induce cellular insulin resistance levels, by concerted effects on adipocyte FFA uptake [44] , recy- via their effects on NF- B [21] or Jun-kinase [22] , in part via ser- cling [45, 46] , and release [47] that, together, lead to increased ine phosphorylation of the Insulin Receptor Substrates 1 and 2 lipid partitioning from the rest of the body to adipose tissue. [23] . Recently, two more molecules produced by fat have been TZDs also affect the gene expression of adipocyte-secreted suggested to play a role in glucoregulation. Retinol binding pro- products, inducing adiponectin [48, 49] , while decreasing lep- tein 4 (RBP4), although largely produced in liver, is also made by tin [50, 51] , RBP4 [24] , and resistin [18, 52] . Of note, PPAR is adipocytes, with increased levels in obesity contributing to also expressed at high levels in macrophages, where its role in impaired insulin action [24] . Although the mechanism by which lipid storage is analogous to its function in adipose tissue RBP4 regulates glucose homeostasis is unknown, retinoids are [53, 54] . PPAR ligands also have anti-infl ammatory actions in known to be potent regulators of immunity [25] . Another adi- macrophages, largely via downregulation of gene expression pocyte secreted protein, visfatin, was initially characterized as [55, 56] . pre-B-cell colony-enhancing factor, or PBEF [26] , yet appears to mimic insulin action [27] . Resistin: A mediator of insulin resistance in the rodent Infl ammation and diabetes & & This review is focused on resistin, which we discovered in 2001 In recent years, an unexpected relationship between infl amma- as a TZD downregulated gene in mouse adipocytes [18] . Resistin This document was downloaded for

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