Background: Lipocalin-2, a 25-kDa secreted glycoprotein, is a useful biomarker for early detection of various renal injuries. Because lipocalin-2 is abundantly expressed in adipose tissue and liver, we investigated its relevance to obesity-related pathologies. Methods: We used real-time PCR and in-house immunoassays to quantify the mRNA and serum concentrations of lipocalin-2 in C57BL/KsJ db/db obese mice and their age-and sex-matched lean littermates. We analyzed the association between serum lipocalin-2 concentrations and various metabolic and inflammatory variables in 229 persons (121 men and 108 women) recruited from a previous cross-sectional study, and we evaluated the effect of the insulin-sensitizing drug rosiglitazone on serum lipocalin-2 concentrations in 32 diabetic patients (21 men and 11 women). Results: Compared with the lean littermates, lipocalin-2 mRNA expression in adipose tissue and liver and its circulating concentrations were significantly increased in db/db diabetic/obese mice (P <0.001). These changes were normalized after rosiglitazone treatment. In humans, circulating lipocalin-2 concentrations were positively correlated (P <0.005) with adiposity, hypertriglyceridemia, hyperglycemia, and the insulin resistance index, but negatively correlated (P ‫؍‬ 0.002) with HDL cholesterol. There was also a strong positive association

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Angiopoietin-like protein 4 (ANGPTL4) is a circulating protein predominantly expressed in adipose tissue and liver. Several recent studies demonstrated that ANGPTL4 is the target gene of peroxisome proliferation activators, the agonists of which are widely used as the antidiabetic and lipid-lowering drugs. Here we provide evidence that ANGPTL4 is a blood-borne hormone directly involved in regulating glucose homeostasis, lipid metabolism, and insulin sensitivity. Adenovirus-mediated expression of ANGPTL4 potently decreased blood glucose and improved glucose tolerance, whereas it induced hyperlipidemia, fatty liver, and hepatomegaly in C57 mice. In db͞db diabetic mice, ANGPTL4 treatment reduced hyperglycemia to a normal level, and markedly alleviated glucose intolerance and hyperinsulinemia. Ex vivo studies on primary rat hepatocytes revealed that ANGPTL4 significantly decreased hepatic glucose production and enhanced insulin-mediated inhibition of gluconeogenesis. Serum levels of ANGPTL4 in human subjects inversely correlated with plasma glucose concentrations and HOMA IR, the homeostasis model assessment of insulin resistance. In patients with type 2 diabetes, serum levels of ANGPTL4 were significantly lower than those in healthy subjects, suggesting that the decreased ANGPTL4 could be a causative factor of this disease. These results collectively indicate that ANGPTL4 exerts distinct effects on glucose and lipid metabolism, and that its beneficial effect on glucose homeostasis might be useful for the treatment of diabetes.adipokine ͉ diabetes ͉ fatty liver ͉ metabolism A dipose tissue is now recognized to be an important endocrine organ that secretes a variety of bioactive peptides, known as adipokines (or adipocytokines). Growing evidence suggests that adipokines are critically involved in regulating energy metabolism, systemic insulin sensitivity, cardiovascular tone, and immune response (1, 2). Several adipokines, such as TNF-␣, resistin, and IL6, play causative roles in the pathogenesis of insulin resistance, type 2 diabetes, and thrombotic diseases (1). On the other hand, leptin and adiponectin possess many beneficial functions on energy metabolism and insulin sensitivity. Leptin has long been viewed as an antiobesity hormone (3), whereas adiponectin is an insulin-sensitizing adipokine with direct antidiabetic, antiatherogenic, and antiinflammatory functions (4).Angiopoietin-like protein 4 (ANGPTL4), also known as peroxisome proliferator-activated receptor ␥ (PPAR␥) angiopoietinrelated protein, fasting-induced adipose factor, or hepatic fibrinogen͞angiopoietin-r elated protein, is a recently identified adipokine that is predominantly expressed in adipose tissue and liver (5-7). Mouse ANGPTL4 is composed of an NH 2 -terminal coiled-coil domain and a carboxyl fibronectin-like motif, a structural organization conserved in both angiopoietins and angiopoietin-like proteins (5). ANGPTL4 was originally identified as the target gene of PPAR (5, 6). The agonists of both PPAR␥ and PPAR␣ could enhance ANGPTL4 express...

Adiponectin, an adipocyte-specific secretory protein, is present in serum as three oligomeric complexes. Apart from its roles as an anti-diabetic and anti-atherogenic hormone, adiponectin has been implicated as an important regulator of cell growth and tissue remodeling. Here we show that some of these functions might be mediated by the specific interactions of adiponectin with several important growth factors. Among six different growth factors examined, adiponectin was found to bind with platelet-derived growth factor BB (PDGF-BB), basic fibroblast growth factor (FGF), and heparinbinding epidermal growth factor-like growth factor (HB EGF) with distinct affinities. The bindings of adiponectin with these growth factors are oligomerization-dependent. PDGF-BB bound to the high molecular weight (HMW) and middle molecular weight (MMW) complexes, but not to the low molecular weight (LMW) complex of adiponectin. Basic FGF preferentially interacted with the HMW form, whereas HB EGF bound to all three forms with comparable affinities. These three growth factors did not compete with each other for their bindings to adiponectin, suggesting the involvement of distinct binding sites. The interactions of adiponectin with PDGF-BB, basic FGF, and HB EGF precluded the bindings to their respective membrane receptors and attenuated the DNA synthesis and cell proliferation induced by these growth factors. Small interfering RNA-mediated down-regulation of adiponectin receptors did not affect the suppressive effects of adiponectin on cell proliferation stimulated by these growth factors. These data collectively suggest that the oligomeric complexes of adiponectin can modulate the biological actions of several growth factors by controlling their bioavailability at a pre-receptor level and that this effect might partly account for the anti-atherogenic, anti-angiogenic, and anti-proliferative functions of adiponectin.Adiponectin (also called AdipoQ, ACRP30, GBP28, and aPM1) is an abundant circulating hormone predominantly expressed from adipose tissue (1-4). The protein belongs to the complement factor C1q-like superfamily and is composed of an NH 2 -terminal collagenous region (with a 22-GXY repeat) and a COOH-terminal globular domain. We have previously demonstrated that several conserved lysine residues within the collagenous domain of adiponectin are hydroxylated and glycosylated by the addition of a glucosyl-␣-1,2-galactosyl group (5, 6). In the circulation, adiponectin forms different oligomeric complexes, including high molecular weight (HMW), 1 middle molecular weight (MMW), and low molecular weight (LMW) species (5, 7-9). Growing evidence suggests that adiponectin is an insulin-sensitizing hormone with direct anti-diabetic, antiatherogenic, and anti-inflammatory activities.The circulating levels of adiponectin are decreased in obese individuals and patients with type 2 diabetes, hypertension, and coronary heart diseases (10 -13). Adiponectin replacement therapy has been shown to decrease hyperglycemia and hypertriglyceridemia,...