Bethea Maigen, Cook Tyler, Mommandi Marwa, McClennan Andrew, Martin Allison, Hendrix Jasmine J, Hutch Chelsea R, Lewis Alfor, Seeley Randy J, Fenselau Henning, da Silva Teixeria Silvania, Sandoval Darleen A
Department of Pediatrics, Nutrition Section, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Surgery, University of Michigan, Ann Arbor MI, 48109, USA.
Mol Metab. 2025 Dec;102:102260. doi: 10.1016/j.molmet.2025.102260. Epub 2025 Sep 25.
Chemical and mechanical signals from the gastrointestinal tract are critical for regulating satiety and glucose metabolism. While both nutrient sensing in the intestine and gastric distension has been well studied, the role of intestinal stretch in these metabolic processes remain unclear. This study evaluates the role of intestinal stretch in regulating food intake and glucose homeostasis in the context of normal body weight, obesity, and weight loss occurring via both dietary intervention and vertical sleeve gastrectomy (VSG).
We used the nonnutritive substance mannitol to selectively induce intestinal stretch in conscious mice. We assessed food intake, glucose tolerance, and neuronal activation in mice with normal body weight, obesity, or after dietary or surgically-induced weight loss. We employed chemogenetic approaches to inhibit GLP-1R and OxtR-expressing vagal afferents, and genetic and pharmacological strategies to ablate GLP-1 signaling to explore mechanisms for mannitol-induced suppression of feeding.
Mannitol-induced intestinal stretch acutely suppressed food intake and improved oral glucose tolerance independent of GLP-1 signaling and vagal intestinal mechanosensation. Diet induced obesity impairs mannitol-induced intestinal stretch reductions in food intake and attenuates neuronal activation in the nucleus of the solitary tract (NTS) upon induction of intestinal stretch. Both dietary and surgical weight loss restored intestinal stretch-induced feeding suppression and enhanced NTS neuronal activation. Importantly, VSG heightened NTS neuronal activation in response to oral but not IP glucose.
Together, these data demonstrate that intestinal stretch contributes to the regulation of feeding and glucose metabolism independently of intestinal nutrient-sensing or classical gut hormones.
