TRENDSin Endocrinology & Metabolism Vol.13 No.1 January/February 2002 http://tem.trends.com 1043-2760/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(01)00522-7 18 Review Insulin resistance is defined as a failure of target tissues (adipose, liver, skeletal and cardiac muscle) to respond normally to insulin [1]. At the molecular level, this resistance can occur anywhere in the insulin signaling pathway, from receptor binding to downstream signaling events. Obesity-associated insulin resistance is manifested by increased hepatic glucose output and reduced glucose disposal in peripheral tissues at a given level of insulin [2]. Quantitatively, skeletal muscle is the most important site of insulin-mediated glucose disposal [3]. Adipose tissue clearly plays a significant role in the pathogenesis of insulin resistance, as shown by the high correlation between obesity and insulin resistance [2]. Obesity-induced insulin resistance is affected both by the total amount of adipose tissue and its distribution [4]. Both visceral and deep subcutaneous adipose tissues are associated with insulin resistance [5]. Excessive free fatty acids (FFAs) released by lipolysis from adipose tissue have been implicated in non-insulin dependent diabetes mellitus. FFAs compete with glucose for oxygen and inhibit whole body glucose disposal via the ‘Randle cycle’ [6]. FFAs have a deleterious effect on insulin uptake by the liver and contribute to the increased hepatic glucose release [7]. The concept that signals emanating from adipose tissue regulate organismal glucose homeostasis has been reinforced by the observation that adipose-specific changes in gene expression alter insulin sensitivity in muscle and liver in the mouse [8]. Adipose tissue as an endocrine organ Adipose tissue is the body’s largest reserve of fuel, storing energy in the form of triacylglycerides. This energy can be rapidly mobilized during starvation and other times of need. The switch from energy storage to mobilization within adipocytes is regulated by hormonal signals from other tissues and organs, including the pancreas (insulin), the sympathetic nervous system (catecholamines) and the adrenal glands (glucocorticoids). Until recently, adipocytes were viewed as playing a passive role in fuel homeostasis, with obesity being a consequence of chronic positive energy balance. However, it is now recognized that the endocrine function of adipose tissue is a crucial determinant of energy balance. The discovery of leptin as an adipocyte-derived peptide hormone, the absence of which causes massive obesity in mice [9] and humans [10], conclusively established the endocrine function of adipose tissue. Characterization of the leptin receptor and its mutation in obese mice [11] and people [12] reinforced the notion of adipocytes as a key component of a classical endocrine system with the hypothalamus as a major target tissue [13]. The actions of leptin on the brain include not only regulation of satiety [14–16] but also efferent pathways controlling metabolism [17] and other endocrine systems involved in the starvation response [18]. The discovery of the leptin endocrine system triggered a conceptual shift leading to increased interest in other adipocyte products as signaling molecules. These include FFAs, the elevated levels of which in obesity are probably causally related to reduced insulin action in peripheral tissues [19]. In addition, increasing numbers of proteins are being found to be secreted by adipose tissue, including Acrp30/adiponectin/AdipoQ (herein referred to as Acrp30) [20–22], tumor necrosis factor α (TNF-α) [23], adipsin [24], plasminogen activator-inhibitor [25], acylation-stimulating protein [26], interleukin 6 (IL-6) [27], IL-8 [28], agouti protein [29], transforming growth factor β [30], angiotensinogen [31] and adipophilin [32]. Many of these cytokines and hormones are potential regulators of glucose homeostasis. This review of potential mediators of obesity-associated insulin resistance focuses on the polypeptides that have received the most recent attention, namely: leptin, TNF-α, Acrp30 and IL-6. Potential mediators of obesity-associated insulin resistance Leptin Leptin regulates food intake, body weight, energy expenditure and neuroendocrine function [33,34]. Obesity is a major risk factor for insulin resistance and type 2 diabetes mellitus. Adipocytes secrete numerous substances that might contribute to peripheral insulin sensitivity.These include leptin,tumor necrosis factor α, Acrp30/ adiponectin/ adipoQ and interleukin 6, the potential roles of which are briefly reviewed here. Thiazolidinedione (TZD) antidiabetic drugs regulate gene transcription by binding to peroxisome proliferator activated receptor γ,a nuclear hormone receptor found at its highest levels in adipocytes. A search for genes that are downregulated by TZDs in mouse adipocytes led to the discovery of an adipose-specific secreted protein called resistin. Resistin circulates in the mouse, with increased levels in obesity, and has effects on glucose homeostasis that oppose those of insulin. Thus, resistin is a potential link between TZDs, obesity and insulin resistance in the mouse. Future studies must address the mechanism of action and biological role of resistin and related family members in mice and humans. Claire M. Steppan Mitchell A. Lazar* Division of Endocrinology, Diabetes, and Metabolism, Depts of Medicine and Genetics and The Penn Diabetes Center, University of Pennsylvania Medical Center, Philadelphia, PA 19104-6149, USA. * e-mail: lazar@ mail.med.upenn.edu Resistin and obesity-associated insulin resistance Claire M. Steppan and Mitchell A. Lazar