Sleeve gastrectomy induces adipose browning via suppression of Asprosin and activation of the ATF3-Nrf2/HO-1 axis.

Abstract

Vertical sleeve gastrectomy (VSG) produces rapid metabolic improvement in obesity and type 2 diabetes mellitus (T2DM), yet the molecular basis linking surgery to adipose remodeling remains unclear. The fasting-induced adipokine Asprosin is implicated in metabolic dysregulation, but its role in white adipose tissue (WAT) browning after VSG is unknown. Asprosin expression was assessed in human adipose tissues and longitudinally after VSG. A high-fat diet/streptozotocin-induced rat model with obesity and diabetes and differentiated 3T3-L1 adipocytes were used for in vivo and in vitro mechanistic studies, including AAV-mediated knockdown, pharmacological inhibition, CUT&Tag, and luciferase assays. Asprosin was elevated in obesity and reduced after VSG. In rats, VSG improved metabolic parameters and promoted WAT browning, accompanied by suppression of Asprosin and activation of ATF3-Nrf2/HO-1 signaling. Mechanistically, ATF3 was associated with increased Nrf2 promoter activity and appears to contribute to Asprosin-dependent regulation of thermogenic gene expression. Asprosin knockdown enhanced VSG-induced browning in a HO-1-dependent manner. These findings suggest a potential link between Asprosin suppression and activation of the ATF3-Nrf2/HO-1 axis during VSG-induced adipose browning. VSG is associated with WAT browning, which may involve suppression of Asprosin and activation of the ATF3-Nrf2/HO-1 axis, providing mechanistic insight into metabolic improvement after bariatric surgery. ClinicalTrials.gov identifier NCT07008274.