Circulating Glucagon-like Peptide-1 (GLP-1) Inhibits Eating in Male Rats by Acting in the Hindbrain and Without Inducing Avoidance

Abstract

To address the neural mediation of the eating-inhibitory effect of circulating glucagon-like peptide-1 (GLP-1), we investigated the effects of 1) intra-fourth ventricular infusion of the GLP-1 receptor antagonist exendin-9 or 2) area postrema lesion on the eating-inhibitory effect of intrameal hepatic portal vein (HPV) GLP-1 infusion in adult male rats. To evaluate the physiological relevance of the observed effect we examined 3) the influence of GLP-1 on flavor acceptance in a 2-bottle conditioned flavor avoidance test, and 4) measured active GLP-1 in the HPV and vena cava (VC) in relation to a meal and in the VC after HPV GLP-1 infusion. Intrameal HPV GLP-1 infusion (1 nmol/kg body weight-5 min) specifically reduced ongoing meal size by almost 40% (P < .05). Intra-fourth ventricular exendin-9 (10 μg/rat) itself did not affect eating, but attenuated (P < .05) the satiating effect of HPV GLP-1. Area postrema lesion also blocked (P < .05) the eating-inhibitory effect of HPV GLP-1. Pairing consumption of flavored saccharin solutions with HPV GLP-1 infusion did not alter flavor acceptance, indicating that HPV GLP-1 can inhibit eating without inducing malaise. A regular chow meal transiently increased (P < .05) HPV, but not VC, plasma active GLP-1 levels, whereas HPV GLP-1 infusion caused a transient supraphysiological increase (P < .01) in VC GLP-1 concentration 3 minutes after infusion onset. The results implicate hindbrain GLP-1 receptors and the area postrema in the eating-inhibitory effect of circulating GLP-1, but question the physiological relevance of the eating-inhibitory effect of iv infused GLP-1 under our conditions.

Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia

“…Systemic Ex4 activates GLP-1R receptors on the vagus nerve that in turn activate hindbrain NST relays; NST injections of Ex9 have been shown to impede satiation responses to gastric distension and hepatic portal glucose infusions (Hayes et al, 2009;Punjabi et al, 2014;Rüttimann et al, 2010). The PBN receives prominent and overlapping input from the rostral gustatory and caudal visceral sensory regions of the NST (Baird et al, 2001b;Fulwiler and Saper, 1984 and we have shown that gastric distension and gustatory stimuli modify electrophysiologically recorded neural impulse rates within the LPBN (Baird et al, 2001a, b), suggesting that PBN lesions would likely affect visceral and/or gustatoryrelated responses potentially affected by systemic Ex4.…”

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

“…Consequently, results vary substantially between studies and some suggest that GLP-1 in the circulation can reach any part of the brain, whereas others claim that GLP-1 is restricted to areas of the brain with a leaky BBB (44,72). The latter view was further substantiated by the finding that lesioning the area postrema blocked the effect of hepatoportal vein GLP-1 infusion (76). Additionally, in most rodent studies, peripherally administered GLP-1 retained its satiety effect after vagotomy or vagal deafferentation (33,108).…”

“…Their findings suggest that the permeability of the BBB might be irrelevant for postprandial release of GLP-1 because rats that consumed a 3-g meal within 5-6 min, showed significant elevations in plasma GLP-1 only in the hepatoportal vein and not in the vena cava (76). This would suggest that under physiological conditions, GLP-1 receptors within the CNS are only reached by brain-derived GLP-1, suggesting a fundamental role for the PPG neurons.…”

GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment

“…Likewise, when injected systemically, GLP-1 receptor agonists do not only affect the pancreas and gastrointestinal tract, but probably also the CNS. Thus, the nausea induced by peripheral administration of GLP-1 or exenatide (a GLP-1 agonist) seems to be caused by its direct action in certain brain regions (6,7); and some effects of the drug are mediated by the vagal afferents (8).…”