Abstract
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 (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 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 HSPA12A deficiency whereas promoted by HSPA12A overexpression. Importantly, PPARγ inhibition by GW9662 reversed the HSPA12A-mediated adipocyte differentiation. On the other hand, HSPA12A 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 HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. HSPA12A inhibition might represent a viable strategy for the management of obesity in humans.
Highlights
These authors contributed : Xiaojin Zhang, Xuan ChenEdited by M
Immunoblotting revealed a high level of Heat shock protein A12A (HSPA12A) expression in adipose tissues, including inguinal white adipose tissues (WAT), visceral WAT, peri-renal WAT, and brown adipose tissue (BAT)
Heat shock proteins are an evolutionarily conserved superfamily comprising a group of structurally unrelated subfamilies, including HSPA/HSP70, HSPB/HSP27, HSPC/ HSP90, HSPH/HSP110, and NDAJ/HSP40 [28]
Summary
Peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily of liganddependent transcription factors, is considered to be a master regulator of adipocyte differentiation [4, 6,7,8,9]. PPARγ and C/EBPα positively feeds back to amplify their own expression, and these transcription factors are integral to the activation of the downstream target genes that initiate the adipogenic program. It works in concert with C/EBPα, PPARγ expression is necessary and sufficient for adipogenesis [8]. Our findings imply that HSPA12A is a novel regulator of adipocyte differentiation and diet-induced obesity through a positive feedback regulation with PPARγ. HSPA12A inhibition might represent a viable strategy for the therapy of obesity in humans
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