333-OR: Regulation of Adiponectin Receptor 2 Expression and Function in the Liver

Abstract

Adiponectin, an adipokine, has been implicated in improving lipid and glucose metabolism and preventing diet-induced inflammation. Adiponectin transduces its effects by binding to its cognate receptors, AdipoR1 and AdipoR2. Compared to AdipoR1, AdipoR2 is specifically and heavily expressed in liver tissues, but its function in regulating Adiponectin-mediated signaling remains controversial. Our study indicates that AdipoR2 expression levels are reduced under feeding conditions as compared to fasting, suggesting that nutrition status regulates AdipoR2 expression. We also found that the levels of AdipoR2 in liver tissue are significantly less in mice fed with high fat diets compared to mice on chow diets, indicating down-regulation of AdipoR2 expression is associated with overnutrition-induced insulin resistance. Interestingly, we found that AdipoR2 undergoes protein palmitoylation, a diet-induced post-translational modification important in regulating protein trafficking and stability. By checking potential palmitoylation sites in AdipoR2, we identified several cysteine residues near the N-terminus that could be potential sites of palmitoylation. Site-direct mutagenesis studies indicated that C11A mutant, which mimics de-palmitoylation status at this residue, was more stable and had less plasma membrane located compared to the wild type receptor. Together, our results suggest that diet-induced palmitoylation of AdipoR2 is one of the mechanisms underlying high fat diet-triggered down-regulation of AdipoR2. This study provides critical information for understanding regulation of adiponectin signaling in liver and the potential theraputical values for treating insulin resistance and type 2 diabetes. Disclosure J. Hadley: None. D. A. Scruggs: None. J. Ryu: None. L. Q. Dong: None.