The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.

Obesity-associated diabetes is epidemic in industrialized societies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in adipose tissue and the presumed molecular target for antidiabetic thiazolidinedione drugs that reverse insulin resistance but also promote weight gain. Phosphorylation reduces the activity of PPARgamma in vitro, but physiological relevance has not been demonstrated. We have studied mice homozygous for a mutation (S112A) that prevents PPARgamma phosphorylation. Surprisingly, the weights and adipose mass of PPARgamma-S112A mice are not greater than wild-type. Remarkably, however, genetic prevention of PPARgamma phosphorylation preserves insulin sensitivity in the setting of diet-induced obesity. Underlying this protection are smaller fat cells, elevated serum adiponectin, and reduced free fatty acid levels. Thus, the phosphorylation state of PPARgamma modulates insulin sensitivity. Compounds that prevent PPARgamma phosphorylation or ligands that induce the conformation of nonphosphorylated PPARgamma may selectively enhance insulin sensitivity without increasing body weight.

Resistin is an adipocyte-secreted protein that circulates at increased levels in obesity. Acute administration of resistin impairs glucose tolerance, but the effects of chronic hyperresistinemia have not been established. Here we describe the generation and characterization of transgenic mice that have high circulating levels of resistin in the setting of normal weight. Fasted blood glucose was higher in resistin-transgenic mice than in their nontransgenic littermates, and glucose tolerance was impaired in the hyperresistinemic mice. Metabolic studies in the setting of a hyperinsulinemic-euglycemic clamp protocol revealed that chronically hyperresistinemic mice have elevated glucose production. This increase in glucose production may be partly explained by increased expression of hepatic phosphoenolpyruvate carboxykinase. Thus, chronic hyperresistinemia impairs normal glucose metabolism. Diabetes 53: [1937][1938][1939][1940][1941] 2004 T ype 2 diabetes is an epidemic metabolic disease that is predicted to afflict nearly one-third of people born in the U.S. in the year 2000 sometime during their lives (1). The disease is characterized by tissue resistance to the actions of insulin and is associated with obesity (2). Obese patients without diabetes commonly develop the metabolic syndrome, the hallmark of which is insulin resistance, which appears to be a major risk factor for atherosclerotic cardiovascular disease (3). Thus, the mechanisms by which obesity predisposes to insulin resistance are of tremendous interest.Adipose tissue produces several hormones and cytokines that affect glucose homeostasis (4). Adiponectin and leptin are adipose-specific hormones that improve glucose tolerance. Although produced only in adipose tissue, adiponectin actually circulates at decreased levels in obesity (5). Leptin levels are increased in obesity, although tissues appear to be resistant to its actions (6). Thus, abnormalities in adiponectin and leptin may both contribute to obesity-associated insulin resistance. Several other adipose-derived hormones oppose insulin action, and they circulate at increased levels in obesity, thus also possibly contributing to insulin resistance. Prominent among these are tumor necrosis factor-␣ and interleukin-6, two cytokines that are also produced at high levels in macrophages and were first identified as inflammatory mediators (7,8).Resistin is also produced by adipocytes (9 -11) and circulates at increased levels in obesity (9). Deletion of the resistin gene reduces the impact of obesity on glucose homeostasis (12). Conversely, acute administration of resistin impairs glucose tolerance and insulin action (9,13). Therefore, it is predicted that mice with chronic hyperresistinemia would have impaired glucose metabolism, even in the absence of obesity. This has not been systematically studied, however, and it is quite possible that compensatory mechanisms might overcome the effect of longstanding hyperresistemia. To test this, we created transgenic mice in which circulating resistin level...

The integrin-linked kinase (ILK) is a multifunctional adaptor protein and serine/threonine kinase that binds the cytoplasmic domains of ␤1-and ␤3-integrin receptor subunits (18,19,68). ILK is a key constituent of the molecular bridge between cell surface integrins and the cortical actin cytoskeleton, namely, focal adhesion complexes (32,49,57). In addition to a structural role, integrin-extracellular matrix (ECM) engagement or stimulation with growth factors activates ILK kinase activity in a phosphatidylinositol 3Ј kinase-dependent manner, resulting in phosphorylation of downstream substrates, such as AKT Ser473 and glycogen synthase kinase 3␤ Ser9 (13). ILK also provides integrins with a connection to certain receptor tyrosine kinases via the adaptor proteins PINCH1/2 and NCK2 (64, 72). Overexpression of ILK in cell lines results in anchorage-independent growth, E-cadherin loss, increased invasiveness, and tumorigenicity in nude mice (13,19). Moreover, increased ILK expression and activity in mouse mammary tumor virus ILK transgenic mice leads to mammary hyperplasias and breast cancers (67). These data suggest that ILK activity must be regulated carefully for effective tumor suppression in vivo and raise the possibility that modulators of ILK function or kinase activity could be deregulated during epithelial oncogenesis.Parvin-␣, -␤, and -␥ comprise a small family of widely expressed ILK-binding proteins with tandem calponin homology domains (30,48,51,57,70). The two best-characterized members, Parvin-␣ and -␤, interact directly with the ILK kinase domain in a mutually exclusive manner (73) and modulate both its kinase activity and connections to the actin cytoskeleton (51), although the molecular mechanisms underlying these actions are only now beginning to emerge (43,66,73). Less is known about Parvin-␥ function.Data from several studies suggest that Parvin-␣ and Parvin-␤ may have divergent actions in the regulation of ILK signaling and cytoskeletal dynamics. For example, Parvin-␣ was reported to facilitate ILK-mediated phosphorylation of AKT Ser473, with subsequent protection from apoptosis (13, 73), whereas Parvin-␤ overexpression in HeLa cells promoted apoptosis (73). Parvin-␤ also inhibited ILK kinase activity and reduced AKT Ser473 and glucogen synthase kinase 3␤ Ser9 phosphorylation in response to epidermal growth factor stimulation, as previously reported by us (43), consistent with negative regulation of ILK signaling. In contrast to Parvin-␣, Parvin-␤ directly bound to the actin-binding protein ␣-actinin and was required for proper focal adhesion formation, lamellipodium maturation, and cell spreading (69, 70). In addition to its reg-* Corresponding author. Mailing address: