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E3 Ligase SMURF2 Promotes Adipogenesis and Improves Obesity Complications by Suppressing TGF-β Signaling
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DOI：10.1016/j.jlr.2026.101061.png)
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Abstract
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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 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.
Keywords:
Obesity
Metabolic Health
Adipogenesis
TGF-β/Smad Pathway
E3 Ligase SMURF2
SMURF2
SMAD ubiquitin regulatory factor 2
HFD
high-fat diet
WAT
white adipose tissue
eWAT
epididymal white adipose tissue
sWAT
subcutaneous white adipose tissue
vWAT
visceral white adipose tissue
SVF
stromal vascular fraction
CHX
cycloheximide
FFA
free fatty acid
T-CHO
total cholesterol
TG
triglyceride
ALT
alanine aminotransferase
AST
aspartate aminotransferase
GTT
glucose tolerance test
ITT
insulin tolerance test
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