Adiponectin and Leptin Affect Cell Cycle Regulation and Adiponectin Receptor Function

Abstract

To establish a molecular link between obesity and cancer we examined the effects of the adipocyte produced peptides leptin (LEP) and adiponectin (ADIPO) on MCF7 cell cycle regulation. p27 levels decreased and increased with LEP and ADIPO, respectively, suggesting adipokine‐mediated MCF7 cell cycle regulation. LEP overcame the effects of ADIPO on p27 protein levels. LEP increased adiponectin receptor (ADIPOR) levels despite inhibiting ADIPO action, suggesting that LEP is stabilizing and inactivating ADIPOR. Inhibition of AKT enhanced ADIPOR protein levels, increased 14‐3‐3/ADIPOR binding and inhibited AMPK phosphorylation. Thus, phosphorylation of ADIPOR by AKT disrupts ADIPOR/14‐3‐3 interactions and promotes ADIPOR degradation. ADIPO induces AMPK‐mediated phosphorylation of p27 at T198 and stabilizes p27 protein, effects similar to those seen after AMPK activation by AICAR. ADIPO and AICAR effects on p27 phosphorylation were inhibited by the AMPK inhibitor compound C. ADIPO also induced decreases in ADIPOR protein levels. Our data suggest that ADIPO and LEP exert antagonistic effects on mammary cell cycle regulation, in part by regulating the function and expression of ADIPOR.