GADD45\u03b1 drives brown adipose tissue formation through upregulating PPAR\u03b3 in mice

Wenjing You,Ye Sun,Yizhen Wang,Teresa G Valencak,Tizhong Shan,Ziye Xu

doi:10.1038/s41419-020-02802-5

Abstract

Stress can lead to obesity and metabolic dysfunction, but the underlying mechanisms are unclear. Here we identify GADD45α, a stress-inducible histone folding protein, as a potential regulator for brown adipose tissue biogenesis. Unbiased transcriptomics data indicate a positive correlation between adipose Gadd45a mRNA level and obesity. At the cellular level, Gadd45a knockdown promoted proliferation and lipolysis of brown adipocytes, while Gadd45a overexpression had the opposite effects. Consistently, using a knockout (Gadd45a−/−) mouse line, we found that GADD45α deficiency inhibited lipid accumulation and promoted expression of thermogenic genes in brown adipocytes, leading to improvements in insulin sensitivity, glucose uptake, energy expenditure. At the molecular level, GADD45α deficiency increased proliferation through upregulating expression of cell cycle related genes. GADD45α promoted brown adipogenesis via interacting with PPARγ and upregulating its transcriptional activity. Our new data suggest that GADD45α may be targeted to promote non-shivering thermogenesis and metabolism while counteracting obesity.

Highlights

Stress can lead to metabolic dysfunction and obesity[1].Obesity has become a global epidemic and is a major risk factor associated with several metabolic syndromes, such as type 2 diabetes, insulin resistance, heart disease, stroke, hyperglycemia, hypertension, and cancer[2,3]
These results indicate that Gadd45a expression is positively correlated with obesity and may represent a potential regulator of lipid metabolism and brown adipogenesis
We have provided functional physiological, histological and cellular evidence to demonstrate that GADD45α deficiency improves energy metabolism and mitochondrial biogenesis in mice

Summary

Introduction

Stress can lead to metabolic dysfunction and obesity[1]. Obesity has become a global epidemic and is a major risk factor associated with several metabolic syndromes, such as type 2 diabetes, insulin resistance, heart disease, stroke, hyperglycemia, hypertension, and cancer[2,3]. Three types of adipocytes, white, brown, and beige or brite adipocytes, have been identified[4]. White adipocytes store excess energy in lipid droplets[5], while beige and brown adipocytes burn lipids to produce heat, counteracting obesity[6,7]. Beige and classical brown adipocytes are characterized by their unique ability to transform mitochondrial energy into heat via uncoupling protein 1 (UCP1)[8,9].

Methods

Results

Conclusion