B56α/Protein Phosphatase 2A Inhibits Adipose Lipolysis in High-Fat Diet-Induced Obese Mice

Lipolysis and lipogenesis are two opposite processes that control lipid storage in adipocytes. Impaired adipose lipolysis has been observed in both obese human subjects and animal models. This study investigated the mechanisms underlying impaired adipose lipolysis in a high-fat diet-induced obese (DIO) mouse model. DIO models were created using male C57BL/6 mice. Our results show that beta 3 adrenergic receptor-specific agonist BRL37344 induced adipose lipolysis was significantly blunted in DIO mice. The levels of Ser660 phosphorylation of hormone-sensitive lipase (HSL) were significantly decreased in the epididymal fat of DIO mice. However, protein levels of HSL, adipose triglyceride lipase and its coactivator comparative gene identification-58 were similar between DIO and control mice. It is known that upon lipolytic hormone stimulation, protein kinase A phosphorylates HSL Ser660 and activates HSL, whereas protein phosphatase 2A (PP2A) dephosphorylates and inactivates HSL. Interestingly, our study shows that high-fat feeding did not alter epididymal fat cAMP and protein kinase A protein levels but significantly increased the expression of the alpha-isoform of PP2A regulatory subunit B' (B56 alpha). To study the role of B56 alpha in obesity-associated lipolytic defect, B56 alpha was overexpressed or knocked down by adenovirus-mediated gene transduction in cultured 3T3-L1CAR Delta 1 adipocytes. Overexpression of B56 alpha significantly decreased HSL Ser660 phosphorylation. In contrast, knocking down B56 alpha increased hormone-stimulated HSL activation and lipolysis in mature 3T3-L1CAR Delta 1 adipocytes. These results strongly suggest that elevated B56 alpha/PP2A inhibits HSL and lipolysis in white adipose tissue of DIO mice. (Endocrinology 151: 3624-3632, 2010)