Prospective interventional study in 28 women with obesity completing 36-week semaglutide (2.4 mg/week) followed by 12-week withdrawal, with parallel HFD rat studies, investigating metabolic mechanisms underlying post-semaglutide weight regain. Semaglutide withdrawal was associated with gut microbiota dysbiosis, altered bile acid profiles, and central nervous system appetite regulatory changes that drove weight regain. Provides mechanistic insight into why weight returns after GLP-1 RA discontinuation in females—identifying gut-brain axis disruption as a target for strategies to sustain weight loss beyond active pharmacotherapy.
Abstract
AIMS: To investigate the metabolic mechanisms underlying weight regain (WR) after semaglutide withdrawal in females with obesity, focusing on gut microbiota, bile acid metabolism, and central nervous system regulation.
MATERIALS AND METHODS: In a prospective, single-arm interventional study, 28 women with obesity finished 36-week semaglutide treatment (2.4 mg/week) followed by 12-week withdrawal. Parallel animal studies used HFD-fed female rats with 4-week semaglutide intervention and 4-week withdrawal. Measurements included body weight, metabolic parameters, gut microbiota composition, bile acid profiles, and hypothalamic gene expression.
RESULTS: During treatment, patients achieved significant weight loss (-16.9 ± 4.8 kg), but 71.4% exhibited WR (+5.1 ± 1.6 kg) post-withdrawal, with 78.5% reporting appetite rebound (≥30% increase in VAS score and a sustained ≥300 kcal/day rise). Animal studies showed post-withdrawal gut microbiota dysbiosis (increased Firmicutes/Bacteroidota ratio, reduced Clostridium sensu stricto 1), decreased ursodeoxycholic acid levels, and downregulated hypothalamic TGR5 expression. Hypothalamic orexigenic signaling (AgRP/NPY) rebounded while anorexigenic pathways (POMC/MC4R) attenuated. Improvements in hepatic and adipose lipid metabolism partially persisted through maintained AMPK/SIRT1 activation and AKT/mTOR suppression.
CONCLUSIONS: The recurrence of WR and increased appetite after semaglutide withdrawal coincided with reversals in gut microbiota and related metabolic profiles. This pattern of changes may implicate gut-derived signals in the reactivation of central appetite pathways, providing a basis for investigating strategies to sustain weight loss.