E3 ligase SMURF2 promotes adipogenesis and improves obesity complications by suppressing TGF-β signaling

Enhanced TGF-β/SMAD signaling causes adipose dysfunction by inhibiting adipogenesis and promoting adipocyte pathological hypertrophy in obesity development. Identifying novel regulators of the TGF-β pathway could significant important for modulating adipose metabolism. While ubiquitination of SMAD attenuates TGF-β signaling, it is still unknown whether this mechanism is involved in regulating adipose function. This study revealed that SMAD proteins undergo ubiquitination and degradation during the early stages of adipogenesis. E3 ligase SMURF2 was identified as the primary regulator in this biological process. In vitro studies demonstrated that SMURF2 deficiency significantly impaired adipogenic differentiation of preadipocytes, whereas SMURF2 overexpression markedly enhanced this process. In mouse studies, SMURF2 overexpression robustly promoted de novo adipogenesis, which in turn conferred resistance to high-fat diet-induced obesity and metabolic disorders. Furthermore, increased SMURF2 expression significantly improved and therapeutically ameliorated dysregulated glucose and lipid metabolism in obese mice. Interestingly, we designed a peptide to inhibit SMAD2 phosphorylation, thereby preventing its ubiquitination by SMURF2. Administration of this polypeptide conferred substantial metabolic benefits in obese mice. Our study uncovers a novel regulatory axis controlling adipose tissue expansion via the TGF-β/SMAD pathway. We anticipate that the findings from this project will provide new targets and insights for intervening in obesity and its metabolic complications.