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

Obesity is one of the most serious public health problems. Peroxisome proliferator-activated receptor γ (PPARγ) 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 encodes a novel member of the HSP70 family. Here, we report that obese patients showed increased adipose expression, which was positively correlated with increase of body mass index. Intriguingly, knockout of Hduanyu184212A (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 PPARγ 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 PPARγ and target adipogenic genes during the differentiation, was suppressed by Hduanyu184212A deficiency whereas promoted by Hduanyu184212A overexpression. Importantly, PPARγ inhibition by GW9662 reversed the adipocyte differentiation. On the other hand, Hduanyu184212A expression was downregulated by PPARγ inhibition but upregulated by PPARγ activation in primary adipocytes. A direct binding of PPARγ 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 Hduanyu184212A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. Hduanyu184212A inhibition might represent a viable strategy for the management of obesity in humans.

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