CDC14 phosphatases control adipogenesis via PPARγ de-phosphorylation

Abstract

Adipogenesis is a finely tuned process requiring an appropriate balance between proliferation and differentiation. We demonstrate that CDC14, a CDK-counteracting phosphatase, regulates adipogenesis and glucose metabolism in mammals. Simultaneous depletion of CDC14A and CDC14B protects against high-fat diet-induced obesity, hepatic steatosis and glucose intolerance in vivo. Lack of these phosphatases blocks differentiation of stem cells into adipocytes, a defect rescued by the PPAR{gamma} agonist troglitazone. Mechanistically, we show that CDC14 counteracts ERK2 and CDK5-induced phosphorylation of PPAR{gamma}, a master regulator of adipogenesis, by directly dephosphorylating S112, S273 and T296 residues. This study supports the idea that cell cycle regulators in multicellular organisms evolved to coordinate the balance between proliferation and differentiation in different cell types. Furthermore, since PPAR{gamma} is a key target of anti-diabetic drugs and a central regulator of adipogenesis and metabolism, these findings may have important implications for treatment of metabolic diseases such as type 2 diabetes.