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<p>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 (<i>Glp1r</i><sup><i>-/-</i></sup>Gipr<sup><i>-/-</i></sup>; DIRKO), and glucagon-like peptide double receptor knockout (<i>Glp1r</i><sup><i>-/-</i></sup>Glp2r<sup><i>-/-</i></sup>; 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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月4日

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  • Nadya M. Morrow,
  • Antonio A. Hanson,
  • Claire Fong-McMaster,
  • Dawson B. H. Livingston,
  • Hoda Osman,
  • Lauren Hamilton,
  • Natasha A. Trzaskalski,
  • Cassandra A. A. Locatelli,
  • Mélodie N. Bellefleur,
  • Ethel Messika-Zeitoun,
  • Sebastian M. Cino,
  • Serena M. Pulente,
  • Iryna Abramchuk,
  • Xiaoling Zhao,
  • Ilka Lorenzen-Schmidt,
  • Arianne Morissette,
  • Krista A. Power,
  • Mary-Ellen Harper,
  • Erin E. Mulvihill

摘要

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.