Adiponectin (ADP) is an adipocyte hormone involved in glucose and lipid metabolism. We detected a rise in ADP in cerebrospinal fluid after intravenous (i.v.) injection, consistent with brain transport. In contrast to leptin, intracerebroventricular (i.c.v.) administration of ADP decreased body weight mainly by stimulating energy expenditure. Full-length ADP, mutant ADP with Cys39 replaced with serine, and globular ADP were effective, whereas the collagenous tail fragment was not. Lep(ob/ob) mice were especially sensitive to i.c.v. and systemic ADP, which resulted in increased thermogenesis, weight loss and reduction in serum glucose and lipid levels. ADP also potentiated the effect of leptin on thermogenesis and lipid levels. While both hormones increased expression of hypothalamic corticotropin-releasing hormone (CRH), ADP had no substantial effect on other neuropeptide targets of leptin. In addition, ADP induced distinct Fos immunoreactivity. Agouti (A(y)/a) mice did not respond to ADP or leptin, indicating the melanocortin pathway may be a common target. These results show that ADP has unique central effects on energy homeostasis.

The present study was performed to examine a hypothesis that peroxisome proliferator-activated receptor gamma (PPARgamma) is implicated in high fat diet-induced liver steatosis. Mice were fed with control or high fat diet containing approximately 10% or 80% cholesterol, respectively. Macroscopic and microscopic findings demonstrated that lipid accumulation in the liver was observed as early as 2 weeks after high fat diet and that high fat diet for 12 weeks developed a fatty liver phenotype, establishing a novel model of diet-induced liver steatosis. Gene profiling with microarray and real-time PCR studies demonstrated that among genes involved in lipid metabolism, adipogenesis-related genes, PPARgamma and its targeted gene, CD36 mRNA expression was specifically up-regulated in the liver by high fat diet for 2 weeks. Immunohistochemical study revealed that PPARgamma protein expression is increased in the nuclei of hepatocytes by high fat diet. It was also shown that protein expression of cAMP response element-binding protein (CREB), an upstream molecule of PPARgamma, in the liver was drastically suppressed by high fat diet. All these results suggest for the first time that the CREB-PPARgamma signaling pathway may be involved in the high fat diet-induced liver steatosis.

Resistin was originally reported as an adipose tissuespecific hormone that provided a link between obesity and diabetes. Resistin protein level was elevated in obese mice and decreased by insulin-sensitizing thiazolidinediones. Immunoneutralization of resistin improved insulin sensitivity in diet-induced obese mice, while the administration of exogenous resistin induced insulin resistance. More recently, we have shown that ablation of the resistin gene in mice decreased fasting glucose through impairment of gluconeogenesis, while resistin treatment in these knockout mice increased hepatic glucose production. However, the link between resistin and glucose homeostasis has been questioned by studies demonstrating reduced, rather than increased, resistin mRNA expression in obese and diabetic mice. To better understand the regulation of resistin, we developed a sensitive and specific RIA resistin that could accurately measure serum resistin levels in several mouse models. We show that while resistin mRNA is indeed suppressed in obese mice, the circulating resistin level is significantly elevated and positively correlated with insulin, glucose, and lipids. Both resistin mRNA expression and protein levels in Lep ob/ob mice are suppressed by leptin treatment in parallel with reductions in glucose and insulin. In wildtype mice, serum resistin increases after nocturnal feeding, concordant with rising levels of insulin. Resistin mRNA and protein levels decline in parallel with glucose and insulin during fasting and are restored after refeeding. We performed clamp studies to determine whether resistin is causally related to insulin and glucose. Adipose resistin expression and serum resistin increased in response to hyperinsulinemia and further in response to hyperglycemia. Taken together, these findings suggest that the nutritional regulation of resistin and changes in resistin gene expression and circulating levels in obesity are mediated, at least in part, through insulin and glucose.

We investigated the expression of peroxisome proliferator-activated receptor Q Q (PPARQ Q) and the role of PPARQ Q in cell growth in human gastric cancer cells. Reverse transcriptionpolymerase chain reaction, Northern blot and Western blot analyses showed that a human gastric cancer cell line, MKN45, expressed PPARQ Q mRNA and protein. Luciferase assay in MKN45 cells showed that troglitazone, a selective ligand for PPARQ Q, transactivated the transcription of a peroxisome proliferator response element-driven promoter. Troglitazone or pioglitazone, selective ligands for PPARQ Q, inhibited the growth of MKN45 cells in a dose-dependent manner. Co-incubation of MKN45 cells with troglitazone induced DNA ladder formation. These results suggest that human gastric cancer cells express PPARQ Q and that activation of PPARQ Q inhibits cell growth and induces apoptosis in gastric cancer cells.z 1999 Federation of European Biochemical Societies.

No abstract