通过PPARγ的正反馈调节，HSPA12A是脂肪细胞分化和饮食诱导的肥胖所必需的。,Cell Death and Differentiation

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通过PPARγ的正反馈调节，HSPA12A是脂肪细胞分化和饮食诱导的肥胖所必需的。
Cell Death and Differentiation ( IF 13.7 ) Pub Date : 2019-02-11 , DOI: 10.1038/s41418-019-0300-2
Xiaojin Zhang ₁ , Xuan Chen ₂ , Tao Qi ₂ , Qiuyue Kong ₂ , Hao Cheng ₂ , Xiaofei Cao ₂ , Yuehua Li ₃ , Chuanfu Li ₄ , Li Liu ₁ , Zhengnian Ding ₂

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肥胖是最严重的公共卫生问题之一。过氧化物酶体增殖物激活受体γ（PPARγ）在肥胖形成的脂肪细胞分化中起主要作用。然而，尚未开发出最佳的抗肥胖药，需要进行更多的研究以鉴定肥胖病发病机理中的新型调节剂。热激蛋白12A（HSPA12A）编码HSP70家族的一个新成员。在这里，我们报道肥胖患者的脂肪HSPA12A表达增加，这与体重指数的增加呈正相关。有趣的是，与野生型（WT）同窝仔猪相比，在小鼠中敲除HSPA12A（Hspa12a-/-）可以减轻高脂饮食（HFD）引起的体重增加，肥胖，高脂血症和高血糖。与WT小鼠相比，在Hspa12a-/-小鼠中观察到胰岛素敏感性增加。HFD诱导的Hspa12a-/-小鼠白色脂肪组织（WAT）中PPARγ及其靶成脂基因的上调也被减弱。功能丧失和功能增强研究表明，HSPA12A缺乏抑制了原代脂肪细胞前体的分化以及分化过程中PPARγ和目标脂肪形成基因的表达，而HSPA12A的过表达促进了这种作用。重要的是，GW9662对PPARγ的抑制作用逆转了HSPA12A介导的脂肪细胞分化。另一方面，在原代脂肪细胞中，HSPA12A表达受PPARγ抑制而下调，但受PPARγ激活而上调。通过染色质免疫沉淀测定法证实了PPARγ与Hspa12a启动子区域中PPAR反应元件的直接结合，并在原代脂肪细胞分化后增加了这种结合。这些发现表明，HSPA12A通过PPARγ的正反馈调节，是脂肪细胞分化和饮食诱导的肥胖的新型调节剂。抑制HSPA12A可能代表了管理肥胖症的可行策略。

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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 (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.

更新日期：2019-02-11

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