Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like Peptide 1 receptor deficiency

Abstract

Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor-deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery.

FIG. 1.

The effect of VSG on body weight and body fat in GLP-1r KO mice. VSG-operated mice (n = 5 VSG; n = 7 sham) show significantly elevated plasma GLP-1 15 min after gavage of a mixed meal (A). After 5 weeks of high-fat feeding, GLP-1r WT and KO mice underwent VSG or sham surgery (n = 8 WT sham; n = 11 WT VSG; n = 12 KO sham; and n = 16 KO VSG). Body weight (B) and weight change from the time of surgery (C) were monitored, and body composition (D and E) was assessed on postoperative day 21. The food intake response to the GLP-1r agonist exendin-4 (F) is shown as the difference between 24-h food intake after exendin-4 and saline treatment. Data are represented as mean ± SEM. *P < 0.05; ***P < 0.001.

FIG. 2.

Metabolic effects of VSG in GLP-1r KO mice. GLP-1r WT and KO mice that received VSG or sham surgery underwent a mixed-meal tolerance test on postoperative day 18 (n = 8 WT sham; n = 11 WT VSG; n = 12 KO sham; and n = 16 KO VSG). Blood glucose (A) was measured after gavage of a standard liquid diet, and plasma insulin was determined at baseline (B) and 15 min (C). Food intake (D) was significantly lower in VSG-operated mice of both genotypes from days 0–3, but by days 28–31 there was no effect of surgery and KO mice consumed less than WT controls. Food choice was assessed by macronutrient selection (n = 6 WT sham; n = 7 WT VSG; n = 9 KO sham; and n = 12 KO VSG), showing that VSG mice of both genotypes decrease fat intake and increase carbohydrate intake (E). Data are represented as mean ± SEM. **P < 0.01; ***P < 0.001.

FIG. 3.

VSG in a new model of GLP-1r deficiency. Expressions of GLP-1r exons 6 and 7 were analyzed in pancreas, lung, and hypothalamus of CMV-Cre (control n = 6) and GLP-1r fl^ΔCMV (KO n = 9) mice (A). Mice were tested for their food intake response to the GLP-1r agonist exendin-4 (B). Data are shown as the difference between 24-h food intake after exendin-4 and saline treatment. Body weight change (C) was monitored after VSG or sham surgery (control sham n = 7; control VSG n = 7; KO sham n = 11; KO VSG n = 17), and a mixed-meal tolerance test (D) was conducted 5 weeks postoperatively. Data are represented as mean ± SEM. ***P < 0.001.