Intestinal adaptation to cold-induced metabolic demand and feeding requires GLP-1R and GLP-2R signalling.

Chronic cold exposure in mice increases metabolic demand and food intake; the gut correspondingly expands its absorptive surface area. Gut enteroendocrine cells produce peptide hormones including glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide (GIP) in response to a meal to facilitate nutrient absorption and post-prandial metabolism. The requirement of GLP-1, GLP-2, and GIP receptor signaling for small intestinal adaptations to chronic cold stress has not been investigated. Here, we show that male and female wild-type, double incretin receptor knockout (Glp1r(-/-)Gipr(-/-); DIRKO), and glucagon-like peptide double receptor knockout (Glp1r(-/-)Glp2r(-/-); GLPDRKO) mice consume significantly more food over five weeks in cold (6⁰C) compared to thermoneutral (27 ⁰C; TN) conditions. Jejunal circumference, villi length, and crypt depth are significantly greater with cold-stress in WT and DIRKO mice, but not GLPDRKO mice, compared to TN controls. We show that the GLP-2R is required for jejunal villi length expansion upon cold stress despite significantly elevated plasma active GLP-1 levels. In line with this, GLPDRKO mice fail to gain body weight over the five-week experiment compared to WT controls. Therefore, while GLP-2R action is required for cold stress-induced jejunal villi lengthening, this adaptation is dispensable for body weight gain in the presence of GLP-1R signaling.