Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.

Peripheral administration of glucagon-like peptide (GLP)-1 reduces food intake in animals and humans, but the sites and mechanism of this effect and its physiological significance are not yet clear. To investigate these issues, we prepared rats with chronic catheters and infused GLP-1 (0.2 ml/min; 2.5 or 5.0 min) during the first spontaneous dark-phase meals. Infusions were remotely triggered 2-3 min after meal onset. Hepatic portal vein (HPV) infusion of 1.0 or 3.0 (but not 0.33) nmol/kg GLP-1 reduced the size of the ongoing meal compared with vehicle without affecting the subsequent intermeal interval, the size of subsequent meals, or cumulative food intake. In double-cannulated rats, HPV and vena cava infusions of 1.0 nmol/kg GLP-1 reduced meal size similarly. HPV GLP-1 infusions of 1.0 nmol/kg GLP-1 also reduced meal size similarly in rats with subdiaphragmatic vagal deafferentations and in sham-operated rats. Finally, HPV and ip infusions of 10 nmol/kg GLP-1 reduced meal size similarly in sham-operated rats, but only HPV GLP-1 reduced meal size in subdiaphragmatic vagal deafferentation rats. These data indicate that peripherally infused GLP-1 acutely and specifically reduces the size of ongoing meals in rats and that the satiating effect of ip, but not iv, GLP-1 requires vagal afferent signaling. The findings suggest that iv GLP-1 infusions do not inhibit eating via hepatic portal or hepatic GLP-1 receptors but may act directly on the brain.

Nutrient stimulation of enteroendocrine L cells induces the release of the incretin and satiating peptide glucagonlike peptide 1 (GLP-1). The vagus nerve innervates visceral organs and may contribute to the mediation of gut-derived GLP-1's effects on food intake, energy homeostasis, and glycemic control. To test the hypothesis that vagal afferent neuron (VAN) GLP-1 receptors (GLP-1Rs) are necessary for these effects of endogenous GLP-1, we established a novel bilateral nodose ganglia injection technique to deliver a lentiviral vector and to knock down VAN GLP-1Rs in male Sprague Dawley rats. We found that a full expression of VAN GLP-1Rs is not necessary for the maintenance of longterm energy balance in normal eating conditions. VAN GLP-1R knockdown (kd) did, however, increase meal size and accelerated gastric emptying. Moreover, postmeal glycemia was elevated and insulin release was blunted in GLP-1R kd rats, suggesting that VAN GLP-1Rs are physiological contributors to the neuroincretin effect after a meal. Collectively, our results highlight a crucial role for the VANs in mediating the effects of endogenous GLP-1 on food intake and glycemia and may promote the further development of GLP-1-based therapies.Glucagon-like peptide 1 (GLP-1) is an incretin and satiating hormone that has provided new tools for the pharmacotherapy of obesity and diabetes (1,2). Yet, despite the clinical effectiveness of GLP-1-based drugs in ameliorating the symptoms of type 2 diabetes, the role of endogenous GLP-1 in the control of energy intake and glucose homeostasis is not fully understood. Vagal afferent neurons (VANs) express GLP-1 receptors (GLP-1Rs) (3,4) and terminate in the lamina propria of the intestinal mucosa as well as in the wall of the hepatic portal vein (HPV) (5). VANs may therefore relay the gut GLP-1-derived signals to the brain and, hence, mediate satiating and glucoregulatory responses. Previous studies using lesioning approaches have implicated the vagus nerve in the effects of peripherally administered GLP-1 on food intake and glycemia (reviewed in 6,7). In more recent studies, sudiaphragmatic vagal deafferentation (SDA) in rats clearly attenuated the acute eating-inhibitory effect of intraperitoneally (IP) infused GLP-1 (8) and exendin-4 (Ex-4), a GLP-1R agonist (9). Moreover, unlike Sham-operated rats, SDA rats failed to show a GLP-1R-mediated incretin response (10). Based on these findings, it is reasonable to hypothesize that endogenous gut-derived GLP-1 could activate GLP-1Rs on VANs in a paracrine-like fashion to reduce food intake, limit gastric emptying, and trigger a neural component of the incretin effect. Disruption of this endogenous GLP-1 signaling mechanism in the VANs due to genetic or environmental factors may contribute to the pathophysiology of obesity and diabetes. Hence, we examined the physiological role of in the control of food intake and regulation of glucose homeostasis by generating a specific knockdown (kd) of VAN GLP-1R expression in rats. Our approach is based on the delivery of a...

Ghrelin stimulates food intake and adiposity and thereby increases body weight (BW) in rodents after central as well as peripheral administration. Recently, it was discovered that the gene precursor of ghrelin encoded another secreted and bioactive peptide named obestatin. First reports appeared to demonstrate that this peptide requires an amidation for its biological activity and acts through the orphan receptor, GPR-39. Obestatin was shown to have actions opposite to ghrelin on food intake, BW, and gastric emptying. In the present study, we failed to observe any effect of obestatin on food intake, BW, body composition, energy expenditure, locomotor activity, respiratory quotient, or hypothalamic neuropeptides involved in energy balance regulation. In agreement with the first report, we were unable to find any effect of obestatin on GH secretion in vivo. Moreover, we were unable to find mRNA expression of GPR-39, the putative obestatin receptor, in the hypothalamus of rats. Therefore, the results presented here do not support a role of the obestatin/GPR-39 system in the regulation of energy balance.

Ghrelin is unique among gut peptides in that its plasma level increases during fasts and its administration stimulates eating. Although ghrelin physiology has been intensively studied, whether its eating-stimulatory effect arises from endocrine-neural signal transduction at peripheral or central sites remains unresolved. To address this issue, we tested the effects of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective vagal deafferentation method available, on ghrelin-induced eating. SDA was verified with a cholecystokinin satiation test, retrograde labeling of vagal motor neurons in the dorsal motor nucleus of the vagus with fluorogold, and anterograde labeling of vagal afferents in the nucleus tractus solitarius with wheat germ agglutinin-horseradish peroxidase. Intraperitoneal injections of 10-40 microg/kg ghrelin stimulated eating as robustly in rats with verified complete SDA as in sham-operated controls. Ghrelin also stimulated eating in rats with total subdiaphragmatic vagotomies. We also recorded the electrophysiological responses of gastric load-sensitive vagal afferent neurons to intravenous ghrelin. Ghrelin (10 nmol) phasically (0-30 s) increased activity in two of seven gastric load-sensitive fibers in the absence of gastric loads and tonically (5-30 min) increased activity in only one fiber. Ghrelin did not affect any of the eight fibers tested in the presence of 1-3 ml gastric loads. We conclude that although phasic increases in plasma ghrelin may affect the activity of a fraction of gastric load-sensitive vagal afferents, the acute eating-stimulatory effect of intraperitoneal ghrelin does not require vagal afferent signaling.