Glucagon-like peptide-2 and mouse intestinal adaptation to a high fat diet.

Endogenous glucagon-like peptide-2 (GLP2) is a key mediator of refeeding-induced andresection-induced intestinal adaptive growth. This study investigated the potential roleof GLP2 in mediating the mucosal responses to a chronic high-fat diet (HFD). In thisview, the murine small intestine adaptive response to a HFD was analyzed and a possibleinvolvement of endogenous GLP2 was verified using GLP2 (3–33) as GLP2 receptor (GLP2R)antagonist. In comparison with animals fed a standard diet, mice fed a HFD for 14 weeksexhibited an increase in crypt–villus mean height (duodenum, 27.5G3.0%; jejunum,36.5G2.9%; P!0.01), in the cell number per villus (duodenum, 28.4G2.2%; jejunum,32.0G2.9%; P!0.01), and in Ki67-positive cell number per crypt. No change in the percentof caspase-3-positive cell in the villus–crypt was observed. The chronic exposure to a HFDalso caused a significant increase in GLP2 plasma levels and in GLP2R intestinal expression.Daily administration of GLP2 (3–33) (30–60 ng) for 4 weeks did not modify the crypt–villusheight in control mice. In HFD-fed mice, chronic treatment with GLP2 (3–33) reduced theincrease in crypt–villus height and in the cell number per villus through reduction of cellproliferation and increase in apoptosis. This study provides the first experimental evidencefor a role of endogenous GLP2 in the intestinal adaptation to HFD in obese mice and fora dysregulation of the GLP2/GLP2R system after a prolonged HFD.