Adiponectin has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes. Replenishment of recombinant adiponectin in mice can decrease hyperglycemia, reverse insulin resistance, and cause sustained weight loss without affecting food intake. Here we report its potential roles in alcoholic and nonalcoholic fatty liver diseases in mice. Circulating concentrations of adiponectin decreased significantly following chronic consumption of highfat ethanol-containing food. Delivery of recombinant adiponectin into these mice dramatically alleviated hepatomegaly and steatosis (fatty liver) and also significantly attenuated inflammation and the elevated levels of serum alanine aminotransferase. These therapeutic effects resulted partly from the ability of adiponectin to increase carnitine palmitoyltransferase I activity and enhance hepatic fatty acid oxidation, while it decreased the activities of two key enzymes involved in fatty acid synthesis, including acetyl-CoA carboxylase and fatty acid synthase. Furthermore, adiponectin treatment could suppress the hepatic production of TNF-α and plasma concentrations of this proinflammatory cytokine. Adiponectin was also effective in ameliorating hepatomegaly, steatosis, and alanine aminotransferase abnormality associated with nonalcoholic obese, ob/ob mice. These results demonstrate a novel mechanism of adiponectin action and suggest a potential clinical application of adiponectin and its agonists in the treatment of liver diseases.

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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.

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It has recently been shown that the fat-derived hormone adiponectin has the ability to decrease hyperglycemia and to reverse insulin resistance. However, bacterially produced full-length adiponectin is functionally inactive. Here, we show that endogenous adiponectin secreted by adipocytes is post-translationally modified into eight different isoforms, as shown by two-dimensional gel electrophoresis. Carbohydrate detection revealed that six of the adiponectin isoforms are glycosylated. The glycosylation sites were mapped to several lysines (residues 68, 71, 80, and 104) located in the collagenous domain of adiponectin, each having the surrounding motif of GXKGE(D). These four lysines were found to be hydroxylated and subsequently glycosylated. The glycosides attached to each of these four hydroxylated lysines are possibly glucosylgalactosyl groups. Functional analysis revealed that full-length adiponectin produced by mammalian cells is much more potent than bacterially generated adiponectin in enhancing the ability of subphysiological concentrations of insulin to inhibit gluconeogenesis in primary rat hepatocytes, whereas this insulin-sensitizing ability was significantly attenuated when the four glycosylated lysines were substituted with arginines. These results indicate that full-length adiponectin produced by mammalian cells is functionally active as an insulin sensitizer and that hydroxylation and glycosylation of the four lysines in the collagenous domain might contribute to this activity.In addition to serving as an energy storage depot for triglycerides, adipose tissue is now recognized as an active endocrine organ that can secret a variety of biologically active molecules (adipocytokines) in response to extracellular signals (1-4). Some of these adipocytokines, such as leptin, tumor necrosis factor-␣, and resistin, have been shown to play critical roles in the regulation of systemic energy homeostasis, and altered expression and/or secretion of these adipocytokines may contribute to the causation of insulin resistance, type II diabetes, and its complications such as cardiovascular diseases.Adiponectin (also called ACRP30, adipoQ, and GBP28) is a protein exclusively secreted by adipocytes and was originally cloned by four research groups using different approaches (5-8). Several recent studies suggest that adiponectin might be a critical, long sought after hormone that links obesity, insulin resistance, and type II diabetes (9 -11). The adiponectin gene is located in chromosome 3q27, a susceptibility locus for type II diabetes and related metabolic syndromes (12-14). Circulating adiponectin is abundant in humans as well as rodents, with plasma circulating levels in the microgram/ml range, accounting for ϳ0.01% of the total plasma protein (15, 16). mRNA expression and the secretion level of adiponectin are dramatically decreased in a variety of animal models of insulin resistance as well as in obese humans and type II diabetic patients from different ethnic groups (15)(16)(17)(18)(19)(20). Notably, treatmen...