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

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

  • Cell Death Differ. 2019 Nov;26(11):2253-2267. 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 5 Zhengnian Ding 6
Affiliations

Affiliations

  • 1 Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics,Key Laboratory of Targeted Intervention of Cardiovascular Disease, The First Affiliated Hospital with Nanjing Medical University, 210029, Nanjing, China.
  • 2 Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, 210029, Nanjing, China.
  • 3 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, 210029, Nanjing, China.
  • 4 Department of Surgery, East Tennessee State University, Johnson City, TN, 37614, USA.
  • 5 Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics,Key Laboratory of Targeted Intervention of Cardiovascular Disease, The First Affiliated Hospital with Nanjing Medical University, 210029, Nanjing, China. [email protected].
  • 6 Department of Anesthesiology, The First Affiliated Hospital with Nanjing Medical University, 210029, Nanjing, China. [email protected].
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16578
    99.87%, PPARγ Antagonist