Dampening HPA axis activity enhances the quality and durability of weight loss with GLP-1-based therapies

Obesity is highly prevalent worldwide and is driven by reduced energy expenditure and increased food intake. Consequently, there is growing interest in pharmacological interventions that can mitigate this global burden. Glucagon-like peptide-1 (GLP-1) agonists, such as semaglutide, induce substantial weight loss; however, adverse effects, including loss of lean mass and weight regain following treatment cessation remain poorly understood. We hypothesized that dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis contributes to these adverse effects. Here, we tested whether targeting the HPA axis with a novel corticotropin-releasing hormone (CRH) neutralizing immunotherapy (anti-CRH) could improve the quality and durability of semaglutide-induced weight loss. Male and female C57BL/6J mice were made diet-induced obese, housed in an indirect calorimetry system, and assigned to one of four groups: (1) saline control, (2) semaglutide (40 µg/kg/day, s.c.), (3) anti-CRH (25 mg/kg, i.p., followed by weekly 12.5 mg/kg, i.p.), or (4) semaglutide + anti-CRH. Metabolic outcomes, plasma corticosterone, and glucose tolerance were monitored before, during, and after the 3-week semaglutide treatment period. As anticipated, anti-CRH consistently lowered plasma corticosterone. Semaglutide alone or with anti-CRH reduced body weight and fat mass. Notably, semaglutide induced a marked decrease in lean mass, an effect that was blunted when anti-CRH was co-administered. Following semaglutide withdrawal, mice displayed robust hyperphagia accompanied by rapid recovery of adipose tissue; both of which were attenuated in the combination-treated group and corresponded with increase POMC neuron number and reduced AgRP mRNA in the arcuate nucleus. While studies defining the hypothalamic circuits involved are ongoing, taken together, these findings suggest that dampening HPA axis activity can alleviate key adverse effects of GLP-1R agonists and may offer a strategy to improve both the quality and long-term maintenance of weight loss by reducing circulating corticosterone. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.