Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency

Abstract

Glucagon-like peptide-1 (GLP-1) secretion is greatly enhanced after Roux-en-Y gastric bypass (RYGB). While intact GLP-1exerts its metabolic effects via the classical GLP-1 receptor (GLP-1R), proteolytic processing of circulating GLP-1 yields metabolites such as GLP-1(9-36)amide/GLP-1(28-36)amide, that exert similar effects independent of the classical GLP-1R. We investigated the hypothesis that GLP-1, acting via these metabolites or through its known receptor, is required for the beneficial effects of RYGB using two models of functional GLP-1 deficiency - α-gustducin-deficient (α-Gust (-/-)) mice, which exhibit attenuated nutrient-stimulated GLP-1 secretion, and GLP-1R-deficient mice. We show that the effect of RYGB to enhance glucose-stimulated GLP-1 secretion was greatly attenuated in α-Gust (-/-) mice. In both genetic models, RYGB reduced body weight and improved glucose homeostasis to levels observed in lean control mice. Therefore, GLP-1, acting through its classical GLP-1R or its bioactive metabolites, does not seem to be involved in the effects of RYGB on body weight and glucose homeostasis.

Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms

“…Additionally administration of the GLP-1R antagonist exendin(9-39) increased food intake but did not alter energy expenditure after RYGBP (76). Other investigators found that GLP-1R inactivation did not affect food intake and body weight changes post-RGYBP (77,78); however, such studies utilizing models of functional GLP-1R inactivation should be interpreted with caution in terms of effects on body weight and energy balance, due to the potential confounding effects of lower body weight in GLP-1R knockout mice (77,78). Furthermore, global GLP-1R deletion and central GLP-1R antagonism not only abolish the effects of peripherally produced GLP-1 but also those of centrally produced GLP-1, which itself plays a role in regulating energy homeostasis (79,80).…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Improvements in glucose tolerance following RYGB or VSG in rats are abolished with exendin-9 administration (Chambers et al 2011), all suggesting a role for GLP-1 in the glucose-lowering success of RYGB. Some studies argue against this (Clements et al 2004, Rubino et al 2004, le Roux et al 2007, whereas some have shown that GLP-1 levels do not rise accordingly (Salinari et al 2014), inhibition of GLP-1 signalling has no effect on glycaemia following RYGB (Jimenez et al 2013, Shah et al 2014) and GLP-1R deficient mice still exhibit improved glycaemia following RYGB and VSG (WilsonPerez et al 2013, Mokadem et al 2014). As such, other gut peptides have been implicated as potential contributors to improved glycaemia following bariatric surgery.…”

Hormonal Signaling in the Gut

“…Additionally, responsiveness to GLP-1R agonism in rodents was able to predict improvements in glycemic control following bariatric surgery, independent of weight loss (47). Despite this, both vertical sleeve gastrectomy and RYGB are effective in normalizing glycemia in several models of models of GLP-1R deficiency (48,49), whereas duodenal-jejunal bypass (DJB) improves glucose levels despite nonelevated postsurgical GLP-1 levels in nonobese type 1 diabetic rats (50). Thus, the role of GLP-1 in mediating the antidiabetic effects of bariatric surgery still remains highly controversial (44,45,(51)(52)(53)(54)(55).…”