Cytoplasmic RIP140 negatively modulates adiponectin secretion in adipocytes

Abstract

Receptor‐interacting protein 140 (RIP140) is known as a nuclear co‐repressor for various nuclear receptors. Recently, we identified a PKC epsilon‐triggered post‐translational modification pathway promotes RIP140 cytoplasmic accumulation which in turn blocks GLUT4 trafficking in adipocytes. Here we further examined the roles of cytoplasmic RIP140 in modulating adipokine secretion in adipocytes. We found that silencing RIP140 or PKC epsilon up‐regulated adiponectin secretion but did not affect its mRNA levels. Conditional medium from RIP140‐ or PKC epsilon‐knockdown 3T3‐L1 adipocytes increased glucose uptake in muscle cells as well as decreased glucose production in hepatocytes by promoting AMPK phosphorylation. However, adiponectin neutralized antibody can reverse conditional medium's effect on glucose uptake in muscle cells and glucose production in hepatocytes. Besides, we identified that endothelin‐1 (ET1) enhanced nuclear PKC epsilon activity resulted in RIP140 export from nucleus to cytoplasm, thus exerting its effect on inhibition of adiponectin secretion in adipocytes. Taken together, we demonstred that cytoplasmic RIP140 negatively modulates adiponectin secretion in adipocytes and provided evidence for targeting cytoplasmic RIP140 in adipocytes in promoting systemic insulin sensitivity.NIH grants DK54733, DK60521, DA11190 and K02‐DA13926 to L.‐N.W.