418. rAAV-Mediated Expression of Adiponectin Receptor (AdipoR2) cDNA in Muscle Prevents the Development of Obesity in DIO Rats

Abstract

The adiponectin (Acrp30) is a fat-derived hormone that acts as antidiabetic adipokine. Previously, it had been successfully used to prevent the development of obesity in rodent model (PNAS 2003, v.100, p.14217–14222). The adiponectin receptors, AdipoR1 and AdipoR2, are members of a novel, GPCR-like family of receptors that, upon activation by the ligand, stimulate fatty-acid oxidation and glucose uptake in the liver and muscle. In this study, we investigated the long-term effects of gene therapy of obesity by the adiponectin receptor AdipoR2 cDNA delivered via rAAV1 vector. The rate of body weight (BW) gain and insulin-enhancing effect were tested in diet-induced obese (DIO, Levin's rat) rodent model fed high fat (60%) diet. We have shown that single intramuscular injection of 6x10e12 physical particles of the vector resulted in sustained (up to 160 days) statistically significant (p=0.001) reduction in BW. Distribution of white fat was measured by MRI, intramyocellular (IMCLs) and hepatocellular (HepCLs) lipids composition were monitored by MRS. The endocrine status of the treated rats was assessed using simultaneous multi-analyte detection protocol (LUMINEX), while the ip Glucose Tolerance Test (GTT) was applied to measure the ability of treated rats to withstand glucose challenge. The molecular mechanisms of weight-maintenance resulted from AdipoR2 transgene expression were investigated by assaying downstream signal transduction pathways via AMPK and PPAR-alpha activation. Our data demonstrate the therapeutic physiological effect of the BW reduction mediated by the ectopic expression of adipokine receptor AdipoR2.