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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

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Published on: June 3, 2016

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

Xiaojin Zhang¹, Xuan Chen², Tao Qi²

¹Department 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.

Cell Death and Differentiation

|February 12, 2019

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.

Insights

Heat shock protein 12A (HSPA12A) regulates adipocyte differentiation and obesity. Inhibiting HSPA12A in mice reduced weight gain and improved metabolic health, suggesting HSPA12A as a potential target for obesity management.

Area of Science:

Molecular Biology
Metabolic Diseases
Genetics

Background:

Obesity is a major public health concern with limited effective treatments.
Peroxisome proliferator-activated receptor gamma (PPARγ) is crucial for adipocyte differentiation and obesity development.
Novel regulators of obesity pathogenesis require further investigation.

Purpose of the Study:

To investigate the role of Heat Shock Protein 12A (HSPA12A) in adipocyte differentiation and diet-induced obesity.
To elucidate the relationship between HSPA12A and PPARγ in the context of obesity.

Main Methods:

Analysis of HSPA12A expression in obese patients and correlation with BMI.
Utilized Hspa12a knockout (Hspa12a^-/-) and wild-type (WT) mice fed a high-fat diet (HFD).
Performed loss- and gain-of-function studies on primary adipocyte precursors.
Employed chromatin immunoprecipitation (ChIP) assay to confirm PPARγ binding to the Hspa12a promoter.

Main Results:

Obese patients exhibited increased adipose HSPA12A expression, positively correlated with BMI.
Hspa12a^-/- mice showed attenuated HFD-induced weight gain, adiposity, hyperlipidemia, and hyperglycemia, with improved insulin sensitivity.
HSPA12A deficiency suppressed adipocyte differentiation and PPARγ target gene expression, while HSPA12A overexpression promoted them.
A positive feedback loop between HSPA12A and PPARγ was identified, involving direct PPARγ binding to the Hspa12a promoter.

Conclusions:

HSPA12A acts as a novel regulator of adipocyte differentiation and diet-induced obesity.
HSPA12A positively regulates adipogenesis through a feedback mechanism with PPARγ.
Targeting HSPA12A may offer a potential therapeutic strategy for managing human obesity.

Read full analysis

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