GADD45α drives brown adipose tissue formation through upregulating PPARγ in mice

Stress can lead to obesity and metabolic dysfunction, but the underlying mechanisms are unclear. Here we identify GADD45 alpha, 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 GADD45 alpha 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, GADD45 alpha deficiency increased proliferation through upregulating expression of cell cycle related genes. GADD45 alpha promoted brown adipogenesis via interacting with PPAR gamma and upregulating its transcriptional activity. Our new data suggest that GADD45 alpha may be targeted to promote non-shivering thermogenesis and metabolism while counteracting obesity.