Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice

Abstract

Roux-en-Y gastric bypass (RYGB) causes profound weight loss and remission of diabetes by influencing metabolic physiology, yet the mechanisms behind these clinical improvements remain undefined. After RYGB, levels of glucagon-like peptide-1 (GLP-1), a hormone that enhances insulin secretion and promotes satiation, are substantially elevated. Because GLP-1 signals in both the periphery and the brain to influence energy balance and glucose regulation, we aimed to determine the relative requirements of these systems to weight loss and improved glucose tolerance following RYGB surgery in mice. By pharmacologically blocking peripheral or central GLP-1R signaling, we examined whether GLP-1 action is necessary for the metabolic improvements observed after RYGB. Diet-induced obese mice underwent RYGB or sham operation and were implanted with osmotic pumps delivering the GLP-1R antagonist exendin-(9-39) (2 pmol·kg(-1)·min(-1) peripherally; 0.5 pmol·kg(-1)·min(-1) centrally) for up to 10 wk. Blockade of peripheral GLP-1R signaling partially reversed the improvement in glucose tolerance after RYGB. In contrast, fasting glucose and insulin sensitivity, as well as body weight, were unaffected by GLP-1R antagonism. Central GLP-1R signaling did not appear to be required for any of the metabolic improvements seen after this operation. Collectively, these results suggest a detectable but only modest role for GLP-1 in mediating the effects of RYGB and that this role is limited to its well-described action on glucose regulation.

Keywords: Roux-en-Y gastric bypass; central regulation; glucagon-like peptide-1; glucose tolerance; obesity.

Fig. 1.

Peripheral glucagon-like peptide-1 receptor (GLP-1R) signaling contributes to the improvements in glucose tolerance after Roux-en-Y gastric bypass (RYGB). A: blockade of GLP-1R by chronic exendin-(9–39) (Ex-9) infusion (2 pmol·kg⁻¹·min⁻¹) impaired oral glucose tolerance to a greater extent in RYGB vs. sham mice. B: area under the curve (AUC) calculations for glucose excursion curves after oral glucose administration are shown. Values represent means ± SE. **P < 0.01 and ***P < 0.001, significant differences in comparisons of Sham and RYGB groups treated with Vehicle and Ex-9; #P < 0.05, significant differences in comparisons of weight-matched sham (WMS) with sham and RYGB vehicle-treated groups.

Fig. 2.

Peripheral GLP-1R signaling is not required for improvements in fasting blood glucose or fasting insulin concentrations after RYGB. Fasting blood glucose (A), insulin concentrations (B), homeostasis model assessment of insulin resistance (HOMA-IR; C), and glucose-stimulated insulin secretion (D) were not influenced by chronic Ex-9 infusion in sham or RYGB mice. Values represent means ± SE. *P < 0.05; **P < 0.01.

Fig. 3.

Peripheral GLP-1R signaling is not required for energy balance phenotypes after RYGB. Weight progression over 7 wk (A) and final weight at postoperative week 7 (B) were not altered by blockade of GLP-1R signaling by chronic infusion of Ex-9 in RYGB or sham mice. Cumulative food intake (C and D) over 5 consecutive wk in sham and RYGB mice was also not altered by Ex-9 infusion. Values represent means ± SE. ***P < 0.001, significant differences in comparisons of sham and RYGB groups treated with vehicle and Ex-9; ###P < 0.001, significant differences in comparisons of weight-matched sham (WMS) with sham and RYGB vehicle-treated groups.

Fig. 4.

Acute blockade of central GLP-1 signaling impairs glucose tolerance to a similar extent in RYGB and sham mice. Intracerebroventricular (icv) pretreatment (20 min) with Ex-9 (8 μg/2 μl) impaired oral glucose tolerance in sham (A) and RYGB (C) mice. Area under the curve (AUC) calculations for glucose excursion curves in sham (B) and RYGB (D) mice are shown. Values are means ± SE. *P < 0.05.

Fig. 5.

Chronic blockade of central GLP-1 signaling does not attenuate the improved glucose tolerance or weight loss after RYGB. Chronic blockade of central GLP-1R (0.5 pmol·kg⁻¹·min⁻¹) did not influence oral glucose tolerance (A and B) or oral glucose-stimulated insulin secretion (C and D). Weekly body weight over 4 wk (E) and fat mass after 8 wk (F) of chronic infusion was not altered by Ex-9. Values are means ± SE. *P < 0.05; ***P < 0.001.