Hepatic FMO3 Downregulation Contributes to the Metabolic Benefits of Vertical Sleeve Gastrectomy.

OBJECTIVE:Metabolic bariatric surgery, such as vertical sleeve gastrectomy (VSG), is the most effective treatment for obesity, yet the molecular mechanisms remain incompletely defined. This study aims to explore the role of hepatic flavin monooxygenase 3 (FMO3) in the metabolic improvements of VSG. METHODS:Hepatic FMO3 was assessed in liver biopsies from human patients. Diet-induced obese mice underwent VSG, targeted hepatic FMO3 inhibition with antisense oligonucleotides, or VSG with concurrent FMO3 knockdown. Outcomes included weight loss, glucose tolerance, insulin sensitivity, serum lipids, hepatic steatosis, circulating bile acid profiling, hepatic gene expression involved in the FXR pathway, and bile acid synthesis/transport. RESULTS:In mouse models, VSG suppressed hepatic FMO3 expression, leading to significant weight loss, enhanced glucose and lipid metabolism, and reduced hepatic steatosis. Inhibition of FMO3 using antisense oligonucleotides recapitulated many of these effects, while silencing FMO3 diminished VSG's metabolic benefits. Clinical data revealed elevated hepatic FMO3 expression in patients with obesity and its downregulation after VSG, correlating with metabolic improvements. Additionally, FMO3 downregulation was associated with alterations in bile acid metabolism and FXR signaling. CONCLUSIONS:Hepatic FMO3 downregulation contributes importantly to the metabolic benefits of VSG. Targeting hepatic FMO3 may offer a nonsurgical strategy to reproduce key clinical benefits of metabolic bariatric surgery.