Ssu72 phosphatase orchestrates obesogenic adipogenesis and metabolic homeostasis during nutrient excess

초록

White adipose tissue (WAT) dysfunction under nutrient excess is a central driver of obesity and its related metabolic disorders. Maintaining precise regulation of adipogenesis and lipid metabolism in WAT is essential for systemic energy balance and metabolic health. Here, we identify Ssu72 phosphatase as a critical regulator of adipogenesis required for WAT expansion. Ssu72 expression is elevated in obese WAT. Notably, adipocyte-specific deletion of Ssu72 in mice confers resistance to high-fat diet (HFD)-induced obesity, accompanied by improved insulin sensitivity and altered energy expenditure. Ssu72 deficiency diminishes HFD-induced adipocyte hypertrophy and inflammation in WAT. Mechanistically, loss of Ssu72 inhibits PPAR gamma-mediated adipogenesis and lipid storage by hyperphosphorylation of GSK3 beta, resulting in suppression of WAT expansion. In addition, metabolic alterations in Ssu72-deleted WAT are reversed by restoring Ssu72 expression. Taken together, our findings reveal a novel adipocyte Ssu72-GSK3 beta axis that regulates obesogenic adipogenesis in white adipocytes, suggesting that Ssu72 is a promising target for controlling diet-induced obesity and whole-body metabolic homeostasis.

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