Exenatide-Induced Reduction in Energy Intake Is Associated With Increase in Hypothalamic Connectivity

Abstract

OBJECTIVEGlucagon-like peptide-1 receptor agonists such as exenatide are known to influence neural activity in the hypothalamus of animals and to reduce energy intake. In humans, however, significant weight loss has been observed in only a subgroup of patients. Why only some individuals respond with weight loss and others do not remains unclear. In this functional magnetic resonance imaging (fMRI) study, we investigated differences in hypothalamic connectivity between “responders” (reduction in energy intake after exenatide infusion) and “nonresponders.”RESEARCH DESIGN AND METHODSWe performed a randomized, double-blinded, placebo-controlled, cross-over fMRI study with intravenous administration of exenatide in obese male volunteers. During brain scanning with continuous exenatide or placebo administration, participants rated food and nonfood images. After each scanning session, energy intake was measured using an ad libitum buffet. Functional hypothalamic connectivity was assessed by eigenvector centrality mapping, a measure of connectedness throughout the brain.RESULTSResponders showed significantly higher connectedness of the hypothalamus, which was specific for the food pictures condition, in the exenatide condition compared with placebo. Nonresponders did not show any significant exenatide-induced changes in hypothalamic connectedness.CONCLUSIONSOur results demonstrate a central hypothalamic effect of peripherally administered exenatide that occurred only in the group that showed an exenatide-dependent anorexigenic effect. These findings indicate that the hypothalamic response seems to be the crucial factor for the effect of exenatide on energy intake.

Leptin Substitution in Patients With Lipodystrophy: Neural Correlates for Long-term Success in the Normalization of Eating Behavior

“…Lower scores indicate that hunger feelings (which are often perceived as disturbing) are decreased (18). Of note in this context is that another physiological anorexigenic peptide hormone, the GLP-1 agonist exenatide, had similar effects on the hypothalamus in fMRI connectivity analysis as well as on VAS-assessed hunger and satiety in obese subjects in another study from our group (27). These results combined support the hypothesis that leptin substitution improves homeostatic satiety signaling through the hypothalamus.…”

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

“…Liraglutide effectively lowers body weight in nonobese and obese rats, obese pigs, and humans, and exendin-4 has been show to rapidly circumvent hypothalamic inflammation, all together indicating that nonobese rodents may be a suitable model to describe access to key appetite-regulating neurons (74,79,(84)(85)(86)(87). Also, a clinical study reported an increased hypothalamic connectivity using functional magnetic resonance imaging following a peripheral dose of exenatide (88). The use of neuronal lesion and ablation models has certain limitations, as they interrupt neuronal networks and can potentially induce compensatory responses or affect neuronal functions in distant connected areas.…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Exenatide readily crosses the blood-brain barrier, even more efficiently than native GLP-1 (Kastin & Akerstrom 2003), and it has been shown to activate brain regions involved in food reward and glucose homeostasis when administered subcutaneously (Daniele et al 2015). The effects of exenatide on food intake may be mediated by its central action, as exenatide-induced reductions in energy intake in humans have been associated with increased hypothalamic connectivity (Schlogl et al 2013), and intracerebroventricular injection of the GLP-1R antagonist, exendin-9, blocks the inhibitory effects of exenatide on energy intake in rodents (Kanoski et al 2011). However, the effects of exenatide on glucose regulation do not appear to be dependent on central GLP-1R activation (Lamont et al 2012), and evidence suggests that exenatide may exert its effects on glycaemia through direct action on the pancreas (Smith et al 2014).…”