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

The antidiabetic hormone adiponectin circulates in blood as several oligomeric complexes, and the ratios between them are critical in determining insulin sensitivity. In this study we investigated the role of testosterone in regulating the oligomeric complex distribution of adiponectin. Gel filtration analysis revealed that circulating adiponectin existed as the forms of high molecular weight (HMW), middle molecular weight, and low molecular weight complexes in both human and mice. The concentration of HMW adiponectin in female was significantly higher than that in male, whereas there were no gender differences for the other two forms. Castration induced a dramatic elevation of the HMW form but had no effect on either the middle molecular weight or the low molecular weight form in mice. Testosterone treatment, on the other hand, caused a specific reduction of HMW adiponectin in the circulation. Pulse-chase labeling experiments in rat adipocytes revealed that the three oligomeric forms of adiponectin were secreted into the culture medium at different rates and that testosterone selectively impeded the secretion of HMW adiponectin but not the other two forms. The inhibitory effect of testosterone on secretion of HMW adiponectin was largely restored by the transcription inhibitor actinomycin D, suggesting the involvement of a transcriptional event in this process. The selective inhibition of HMW adiponectin by testosterone might contribute to the sex dimorphism of adiponectin in terms of its oligomeric complex distribution and could partly explain why men have higher risk to insulin resistance and atherosclerosis than women.

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...

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