GLP‐1 induces alpha cell proliferation and overrides leptin suppression induced by negative energy balance in vagotomized rats

Abstract

Glucagon‐like peptide‐1 (GLP‐1) influences energy balance by exerting effects on food intake and glucose metabolism, through mechanisms that are partially dependent on the vagal pathway. The aim of this study was to characterize the effects of chronic GLP‐1 stimulation on energy homeostasis and glucose metabolism in the absence of vagal innervation Truncal vagotomized (VGX) and sham operated rats (SHAM) received an intraperitoneal GLP‐1 infusion (3.5 pmol/kg/min) trough mini‐osmotic pumps. To dissect the effects derived from vagal denervation on food intake, an additional group was included consisting of sham operated rats that were PAIR FED to VGX. Food intake and body weight were recorded throughout the experimental period, while the percentage of white and brown adipose tissue, fasting glucose, insulin, gastro‐intestinal hormonal profile, hypothalamic, and BAT gene expression were assessed at endpoint. VGX rats had significantly lower food intake, body weight gain, and leptin levels when compared with SHAM rats. Despite having similar body weight, PAIR‐FED rats had lower fasting leptin, insulin and insulin resistance, while having higher ghrelin levels than VGX. GLP‐1 infusion did not influence food intake or body weight, but was associated with lower leptin levels in VGX and lower pancreatic α‐cells ki‐67 staining in SHAM. Concluding, this study corroborates that the vagus nerve may modulate whole body energy homeostasis by acting in peripheral signals. Our data suggest that in the absence of vagal or parasympathetic tonus, GLP‐1 mediated inhibition of cell proliferation markers in α‐cells is prevented, meanwhile leptin suppression, associated with a negative energy balance, is partially overridden.

GLP-1 Increases Circulating Leptin Levels in Truncal Vagotomized Rats

“…Prior to surgical procedure, rats were fasted for 12 h, weighed and anaesthetized with sevoflurane (Abbott Laboratories Limited, Maidenhead, UK) (8% for induction, 3% for maintenance). Surgical procedure was performed as previously described [2,21].…”

“…Therefore, rats were handled on a daily basis from 5 days post-surgery and familiarized to the experimental procedures. To confirm that the vagus nerve ablation was successful, a procedure based on the feeding response to cholecystokinin octapeptide (CCK-8) (10 µg/kg ip) (Bachem, St Helens, UK) was used as previously described [2,21]. Further confirmation of vagotomy success or failure was obtained by weighing the rats' stomachs after the sacrifice.…”

“…Resting energy expenditure (REE) was assessed by indirect calorimetry, as previously described [21].…”

“…At the time of sacrifice, basal hypothalamus and interscapular brown adipose tissue (BAT) were collected and immediately frozen by immersion in liquid nitrogen. Total RNA isolation and RNA expression analysis of NPY, AgRP, POMC and CART in the hypothalamus and of UCP-1 in BAT was performed as previously described [21].…”

Impact of Incretin-Based Therapies on Adipokines and Adiponectin

“…There are data suggesting incretin-based therapy has close interactions with leptin expression, secretion, or activities [ 35 , 36 ], interconnected via vagal afferent neurons (VANs) to control feeding and glucose homeostasis [ 37 ]. GLP-1 directly induces centric nuclei involved in leptin secretion and feeding behavior [ 38 ].…”