GLP‐2 receptor expression in excitatory and inhibitory enteric neurons and its role in mouse duodenum contractility

Endogenous glucagon-like peptide-2 (GLP2) is a key mediator of refeeding-induced and resection-induced intestinal adaptive growth. This study investigated the potential role of GLP2 in mediating the mucosal responses to a chronic high-fat diet (HFD). In this view, the murine small intestine adaptive response to a HFD was analyzed and a possible involvement 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 weeks exhibited 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 percent of caspase-3-positive cell in the villus-crypt was observed. The chronic exposure to a HFD also 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-villus height in control mice. In HFD-fed mice, chronic treatment with GLP2 (3-33) reduced the increase in crypt-villus height and in the cell number per villus through reduction of cell proliferation and increase in apoptosis. This study provides the first experimental evidence for a role of endogenous GLP2 in the intestinal adaptation to HFD in obese mice and for a dysregulation of the GLP2/GLP2R system after a prolonged HFD.

Section: Introductionmentioning

confidence: 99%

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

Baldassano¹,

Amato²,

Cappello³

et al. 2013

“…Activation of GLP2 receptors regulates epithelial cell growth (Tsai et al 1997, Bjerknes & Cheng 2001, reduces intestinal permeability, enhances the barrier function (Benjamin et al 2000, Moran et al 2012, Drucker & Yusta 2014, increases mesenteric blood flow (Guan et al 2006, Bremholm et al 2009) and inhibits gastrointestinal motility, thus providing another mechanism to increase digestion and absorption of nutrient (Wøjdemann et al 1998, McDonagh et al 2007, Amato et al 2009, Cinci et al 2011.…”

Section: Overview On Glp2mentioning

confidence: 99%

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

Amato¹,

Baldassano²,

Mulè³

2016

Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells and by a discrete population of neurons in the brainstem, which projects mainly to the hypothalamus. The main biological actions of GLP2 are related to the regulation of energy absorption and maintenance of mucosal morphology, function and integrity of the intestine; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model. Indeed, mice lacking GLP2 receptor selectively in hypothalamic neurons that express proopiomelanocortin show impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis). Moreover, GLP2 acts as a beneficial factor for glucose metabolism in mice with high-fat diet-induced obesity. Thus, the aim of this review is to update and summarize current knowledge about the role of GLP2 in the control of glucose homeostasis and to discuss how this molecule could exert protective effects against the onset of related obesity type 2 diabetes.

“…In addition to promoting expansion of the gastrointestinal mucosal surface area, GLP2 has been shown to affect gastrointestinal motility in humans and rodents. In fact, it inhibits gastric emptying (Wøjdemann et al 1998, Nagell et al 2004, decreases gastric fundic tone leading to enhancing gastric capacity (Amato et al 2009), reduces intestinal transit in vivo (McDonagh et al 2007), and reduces small and large intestinal motility in vitro (Amato et al 2010, Cinci et al 2011. The inhibitory effect on gastric tone, at least in mice, seems to depend on the nutritional state of the animal, being largely more evident in mice fed a high fat diet (HFD), which after 14 weeks develop obesity syndrome (Collins et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2

Baldassano¹,

Bellanca²,

Serio³

et al. 2012

We investigated the potential anorectic action of peripherally administered glucagon-like peptide 2 (GLP2) in lean and diet-induced obese (DIO) mice. Mice, fasted for 16 h, were injected i.p. with native GLP2 or [Gly 2 ]GLP2, stable analog of GLP2, before or after GLP2 (3-33), a GLP2 receptor (GLP2R) antagonist, or exendin (9-39), a GLP1R antagonist. Food intake was measured at intervals 1, 2, 4, 8, and 24 h postinjection. In addition, we tested in lean mice the influence of [Gly 2 ]GLP2 on gastric emptying and the effects of GLP1 alone or in combination with [Gly 2 ]GLP2 on food intake. [Gly 2 ]GLP2 dose dependently and significantly inhibited food intake in lean and DIO mice. The reduction of food intake occurred in the first hour postinjection and it was sustained until 4 h postinjection in lean mice while it was sustained until 2 h postinjection in DIO mice. GLP2 significantly inhibited food intake in both lean and DIO mice but only in the first hour postinjection. ]GLP2 decreased the gastric emptying rate. Results suggest that GLP2 can reduce food intake in mice in the short term, likely acting at a peripheral level. DIO mice are less sensitive to the anorectic effect of the peptide.