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Weight loss reverses obesity-associated impairments in acute gastrointestinal stretch-induced suppression of food intake and glucose homeostasis

Year: 2025
Type: article
Abstract: OBJECTIVE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
DOI: 10.1016/j.molmet.2025.102260
Authors: Maigen Bethea, Tyler Cook, Marwa Mommandi, Andrew McClennan, Allison Martin, Jasmine J. Hendrix, Chelsea R. Hutch, Alfor Lewis, Randy J. Seeley, Henning Fenselau, Silvania Da Silva Teixeira, Darleen A. Sandoval
Institutions: University of Colorado Anschutz, University of Michigan, University of Cologne, Max Planck Institute for Metabolism Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospital Cologne
Language: English
Open Access status: gold
Estimated APC paid: $4,270
Funders: Burroughs Wellcome Fund, National Institutes of Health, Horizon 2020 Framework Programme, European Research Council, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences
Awards: G1229796855, G1625418467, G1855878456, G4541629867, G5344990240, G5471811474, G5474428610, G777521102, The role of diminished CNS hypoglycemia sensing in postbariatric hypoglycemia, Michigan Diabetes Research Center (MDRC), Colorado Clinical and Translational Sciences Institute (CCTSI)
OpenAlex ID: W4414591245
FWCI: 1.054
Cites: 29
Cited by: 3
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