The functional analysis of physiological overexpression of adiponectin in vivo

Abstract

The improved understanding of the physiological relevance of adipocytederived proteins, adipokines, has led to an increased appreciation of the adipose tissue as an endocrine organ. A dysregulation at the level of adipokines can trigger major unfavorable metabolic changes and result in central and peripheral insulin resistance. Of adipokines, adiponectin promotes glucose uptake and beta-oxidation of free fatty acids in the skeletal muscle and represses gluconeogenesis and triglyceride synthesis in the liver, thereby serving as an insulin sensitizer.;In this study, we explored a novel model of improved metabolic profiles through enlarging subcutaneous adipose mass. Interestingly, the presence of already slightly elevated levels of adiponectin in leptin deficient ( ob/ob) mice lead to an increased number of adipocytes of smaller average size characterized by reduced local and systemic inflammation. Among the inflammatory effects, the liver of transgenic ob/ob mice displayed a reduction in steatosis and a dramatic decrease in hepatic diacylglycerol levels. Moreover, adiponectin expression triggered an increased expression of PPARgamma target genes in adipose tissue, a phenomenon likely to contribute to these metabolic improvements. These findings reveal that adiponectin functions as a strong physiological signal enhancing storage of lipid preferentially in adipose tissue rather than other tissues. Consequently, the net effect of adiponectin is to ameliorate systemic insulin resistance through a reduction of ectopic lipid accumulation in the liver and muscle.;Beyond an exclusive metabolic role, we also examined a possible role of adiponectin in female reproduction. The chronic treatment with thiazolidinediones (PPARgamma agonists) has been known to contribute to the elevation of adiponectin in circulation. Impaired ovulation and decreased pregnancy rate were observed in WT female mice during administration of TZD and female mice overexpressing adiponectin whereas the fertility of adiponectin null mice is not affected under these conditions. Our findings suggest that adiponectin is a potential link between metabolic changes and fertility potentially through regulation of the hypothalamic/pituitary/gonadal (HPG) axis.;In conclusion, my work has generated new insights into the function of adiponectin as a "starvation signal" of the fat cells, which primarily mediates lipid deposition and influences reproduction. Both of these findings are rather novel and quite unexpected.