HSPA12A is required for adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPAR gamma

摘要

Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays the master role in adipocyte differentiation for obesity development. However, optimum anti-obesity drug has yet been developed, mandating more investigation to identify novel regulator in obesity pathogenesis. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose HSPA12A expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of HSPA12A (Hspa12a(-/-)) in mice attenuated high-fat diet (HFD)-induced weight gain, adiposity, hyperlipidemia, and hyperglycemia compared to their wild type (WT) littermates. Increased insulin sensitivity was observed in Hspa12a(-/-) mice compared to WT mice. The HFD-induced upregulation of PPAR gamma and its target adipogenic genes in white adipose tissues (WAT) of Hspa12a(-/-) mice were also attenuated. Loss- and gain-of-function studies revealed that the differentiation of primary adipocyte precursors, as well as the expression of PPAR gamma and target adipogenic genes during the differentiation, was suppressed by HSPA12A deficiency whereas promoted by HSPA12A overexpression. Importantly, PPAR gamma inhibition by GW9662 reversed the HSPA12A-mediated adipocyte differentiation. On the other hand, HSPA12A expression was downregulated by PPAR gamma inhibition but upregulated by PPAR gamma activation in primary adipocytes. A direct binding of PPAR gamma to the PPAR response element in the Hspa12a promoter region was confirmed by chromatin immunoprecipitation assay, and this binding was increased after differentiation of primary adipocytes. These findings indicate that HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPAR gamma. HSPA12A inhibition might represent a viable strategy for the management of obesity in humans.