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.

Keywords: GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; Glp1r−/−, glucagon-like peptide-1 receptor deficient mice; Gut hormones; HOMA-IR, Homeostasis Model Assessment-Insulin Resistance; Mouse model; PF-sham, pair-fed sham; RYGB, Roux-en-Y gastric bypass; Taste perception; WM-sham, weight-matched sham; WT, wild-type; Weight-loss surgery; α-Gust−/−, α-gustducin deficient mice.

Figure 1

RYGB-enhanced GLP-1 secretion is attenuated in α-Gust^−/− mice. RYGB greatly enhanced glucose-stimulated GLP-1 in WT mice and this effect was attenuated in α-Gust^−/− mice. Stimulated GLP-1 was reduced in α-Gust^−/− WM-sham compared to sham mice. (n=6, sham; n=6, RYGB; n=6, WM-sham). Values are expressed as mean±SEM. One-way ANOVA was used to compare surgical interventions within a genotype. Student's t-test was used to compare the effect of surgical intervention across genotype. ^⁎P<.05 versus sham; ^#P<.05 versus RYGB; ^@P<.05 α-Gust^−/− versus WT.

Figure 2

RYGB reduces body weight and improves body composition in α-Gust^−/− mice. (A) Body weight, expressed as a percentage of pre-operative values, was reduced in RYGB-treated α-Gust^−/− mice (left) compared to sham and PF-sham mice. RYGB induced a comparable reduction in WT mice (right). (B) Total body weight, (C) fat mass, and (D) lean mass (as measured during post-operative week 5) were reduced after RYGB in α-Gust^−/− mice to levels observed in non-operated, age-matched lean C57BL/6 control mice (Lean (C57)). (n=6–11, sham; n=7–12, RYGB; n=7, PF-sham; n=7, Lean (C57)). Values are expressed as mean±SEM. Two-way ANOVA with repeated measures was used to compare weight over time among surgical interventions within a genotype. One-way ANOVA was used to compare surgical interventions within a genotype. Student's t-test was used to compare RYGB-treated α-Gust^−/− mice and Lean (C57) controls. ^⁎P<.05 versus sham; ^#P<.05 versus RYGB; NS=not significant.

Figure 3

RYGB reduces food intake and increases total energy expenditure in α-Gust^−/− mice. (A) RYGB reduced daily intake in α-Gust^−/− mice from post-operative day 8 through 24. Thereafter, daily intake in RYGB and sham mice was equivalent. (B) RYGB reduced cumulative intake through week 5 in α-Gust^−/− mice. (C) RYGB reduced daily intake in WT mice from day 8 through day 11. (D) Cumulative intake through week 5 was not reduced in WT mice after RYGB. (E) RYGB reduced feeding efficiency and increased (F) total energy expenditure in α-Gust^−/− (left) and WT (right) mice compared to sham and PF-sham. (n=6–7, sham; n=7–9, RYGB; n=7, PF-sham). Values are expressed as mean±SEM. One-way ANOVA was used to compare surgical interventions within a genotype. Student's t-test was used to compare the effect of RYGB on daily intake compared to shams. ^⁎P<.05 versus sham; ^#P<.05, versus RYGB; NS=not significant.

Figure 4

RYGB improves glucose homeostasis in α-Gust^−/− mice. (A) Oral glucose tolerance, (B) glucose-stimulated plasma insulin, (C) insulin tolerance, (D) fasting blood glucose, (E) fasting plasma insulin, and (F) HOMA-IR were improved after RYGB in α-Gust^−/− mice. These parameters in RYGB mice were comparable to WM-shams and lean C57BL/6 controls. (n=4–11, sham; n=6–12, RYGB; n=6–7, WM-sham; n=6–7, Lean (C57)). Values are expressed as mean±SEM. Curves were analyzed by area under the curve analysis, using trapezoidal rule. One-way ANOVA was used to compare surgical interventions within a genotype. Student's t-test was used to compare RYGB-treated α-Gust^−/− mice and Lean (C57) controls. ^⁎P<.05, versus sham; NS=not significant.

Figure 5

RYGB reduces body weight, improves body composition, and increases total energy expenditure in Glp1r^−/− mice. (A) Body weight, (B) fat mass and (C) lean mass were all reduced in Glp1r^−/− mice after RYGB to the level of age-matched lean C57BL/6 control mice [Lean (C57)]. (D) Daily intake was reduced in Glp1r^−/− mice through post-operative day 18 compared to shams, but no difference was observed thereafter. (E) Feeding efficiency was decreased and (F) total energy expenditure was increased after RYGB in Glp1r^−/− mice. [n=9, sham; n=9, RYGB; n=7, Lean (C57)]. Values are expressed as mean±SEM. Student's t-test was used to compare RYGB-treated Glp1r^−/− mice to Glp1r^−/− shams and Lean (C57) controls. ^⁎P<.05, versus sham; NS=not significant.

Figure 6

RYGB improves glucose homeostasis in Glp1r^−/− mice. (A) Oral glucose tolerance (B) insulin tolerance, (C) glucose-stimulated plasma insulin, (D) fasting blood glucose, (E) fasting plasma insulin, and (F) HOMA-IR in RYGB, sham, and WM-sham Glp1r^−/− mice. (n=8–10, shams; n=8–11, RYGB; n=4–7, WM-sham). Values are expressed as mean±SEM. Curves were analyzed by area under the curve analysis, using trapezoidal rule. One-way ANOVA was used to compare surgical interventions within a genotype. ^⁎P<.05, versus sham.