Following the publication of data demonstrating that ICV GLP-1 dose-dependently inhibits food intake A role for glucagon-like peptide-1 in the central regulation of feeding. Nature. 1996 4;379(6560):69-72, subsequent studies demonstrated that blockade of CNS GLP-1 action using ICV infusion of exendin (9-39) increased food intake and promoted weight gain in rats Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology. 1999 140(1):244-50. Similarly, injection of exendin (9-39) into the lateral hypothalamus increased food intake in satiated rats Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2003 Jun;284(6):R1427-35.
Over the last several years, the evidence linking GLP-1 action in the CNS to regulation of food intake and body weight has been confirmed by multiple independent laboratories. Although the PVN of the hypothalamus was the initial focus of studies linking GLP-1 actions to satiety, several studies have now demonstrated, using direct injection approaches, that multiple brain regions are capable of transducing a CNS satiety effect in response to GLP-1, including the LH, DMH, and VMH, as shown in The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci. 2002 Dec 1;22(23):10470-6. and Peptides that regulate food intake: glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats. Am J Physiol Regul Integr Comp Physiol. 2003 Jun;284(6):R1427-35.
The mechanisms transducing the anorectic actions of GLP-1R agonists appear to overlap with those activated by PYY(3-36), but distinct pathways can be identified for these 2 different types of peptides, as illustrated in The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res. 2005 May 17;1044(1):127-31. and Peripheral Exendin-4 and Peptide YY3-36 Synergistically Reduce Food Intake through Different Mechanisms in Mice. Endocrinology. 2005 Jun 2; [Epub ahead of print].
Similarly, infusion of ghrelin in rats dose-dependently attenuates the inhibitory effects of GLP-1 and exendin-4 on food intake as described in Ghrelin Attenuates the Inhibitory Effects of Glucagon-Like Peptide-1 and Peptide YY(3-36) on Food Intake and Gastric Emptying in Rats. Diabetes. 2006 Nov;55(11):3038-46. Conversely, central or peripheral infusion of exendin-4 suppresses levels of plasma ghrelin in fasted rats. Intriguingly, the effects of exendin-4 on ghrelin secretion were not mimicked by native GLP-1, and they were not blocked by the classical GLP-1 receptor antagonist exendin(9-39). These findings implicate a role for a non-classical GLP-1R coupled to regulation of ghrelin secretion as outlined in Exendin-4 potently decreases ghrelin levels in fasting rats. Diabetes. 2007 Jan;56(1):143-51. Similarly infusion of GLP-1 in healthy male human subjects was associated with prevention of the postprandial decline in plasma ghrelin levels and reduced levels of ghrelin for several hours after meal ingestion. The patterns of plasma ghrelin concentrations were inversely related to the plasma levels of insulin and C-peptide, raising the possibility that the actions of GLP-1 on ghrelin may be indirect and mediated via stimulation of insulin secretion. See Glucagon-like peptide 1 (GLP-1) suppresses ghrelin levels in humans via increased insulin secretion. Regul Pept. 2007 Mar 20; [Epub ahead of print]
Peripheral administration of long-acting GLP-1 agonists to diabetic rodents also reduces food intake and achieve weight loss, in studies of several weeks duration. The Novo Nordisk GLP-1 analogue NN2211 (Liraglutide) induced weight loss in both lean control rats and in MSG-lesioned rats, hence the anorectic actions were presumably mediated by signaling systems outside the region of the hypothalamus affected by neonatal monosodium glutamate administration. To review the experimental data, including analyses of body composition after NN2211, see Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats. Diabetes. 2001 Nov;50 (11):2530-2539
Over a dozen human studies in both normal subjects and in patients with obesity or type 2 diabetes have examined the relationship between GLP-1 infusion and food intake, as described in Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol. 1999 May;276(5 Pt 2):R1541-4. The majority of studies have shown a small but significant inhibition of short-term food intake with concurrent GLP-1 infusion. A Meta-Analysis of these studies has concluded that there is a dose-dependent reduction in food intake associated with a reduction of gastric emptying in human subjects. See A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab. 2001 86(9):4382-9
An important but as yet unanswered questions surrounds the effects of intermittent vs. continuous GLP-1 administration on food intake and body weight. GLP-1 given by subcutaneous injection 30 minutes before meals in a 5 day randomized cross-over study of obese human subjects was more effective in producing weight loss relative to a continuous 5 day subcutaneous GLP-1 infusion. However, a key difference between the different arms of the study was the peak plasma level of GLP-1 achieved, which was significantly higher (269.4 vs. 88.7 pM) in the patients given subcutaneous injections. Hence, it is not possible to make firm conclusions as to whether peripheral vs. continuous GLP-1 delivery exerts differential effects on weight loss. See Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects. Br J Nutr. 2004 Mar; 91(3): 439-46
Does activation of the GLP-1 receptor produce weight loss via effects on energy expenditure? Acute administration of exendin-4 to mice inhibited food intake in association with a compensatory reduction in energy expenditure Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004 Aug;127(2):546-58. Similarly, administration of Liraglutide for 7 days to normal rats was associated with weight loss and a reduction in energy expenditure Systemic administration of the long-acting GLP-1 derivative NN2211 induces lasting and reversible weight loss in both normal and obese rats. Diabetes. 2001 Nov;50(11):2530-9. Furthermore, a 4 hour infusion of GLP-1 in 20 normal weight healthy male volunteers reduced resting energy expenditure, primarily due to lower carbohydrate oxidation with no changes in fat or protein oxidation The effect of glucagon-like peptide-1 on energy expenditure and substrate metabolism in humans. Int J Obes Relat Metab Disord. 2000 Mar;24(3):288-98. Comparable reductions in energy expenditure and carbohydrate oxidation were observed following a 4 h GLP-1 infusion in non-diabetic obese subjects studied after ingestion of a breakfast meal The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord. 2001 Jun;25(6):781-92. Similarly, daily administration of the GLP1R agonist Liraglutide to overweight diabetic subjects for 8 weeks was not associated with changes in body weight or 24h energy expenditure as described in The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care. 2004 Aug;27(8):1915-21
Paradoxically, despite the effects of ICV GLP-1on food intake in rodents, GLP-1 receptor-/- CD1 mice are lean and do not exhibit disturbances of food intake or body weight regulation, as shown in Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996 Nov;2(11):1254-8. Furthermore, GLP-1R-/- mice do not develop obesity with age, or following several months of high fat feeding Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice. Endocrinology. 1998 Jul;139(7):3127-32. Hence it seems clear that GLP-1 receptor signaling is not essential, in the context of the knockout mouse, for long term control of body weight.
What are the targets for GLP-1 action in the CNS? GLP-1 depolarized orexin+ neurons in the murine CNS (lateral hypothalamus) but had no effect on MCH+ neurons in the same experiments as outlined in Glucagon-like Peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: implications for viscera-mediated arousal. J Neurosci. 2004 Sep 15;24(37):8141-52
The anorexic actions of exendin-4 and GLP-1 are diminished in fasted rats, yet restored following administration of leptin in the fasted state, implying cross-talk between these signaling systems. Unexpectedly, the exenddin-4-mediated induction of c-fos expression in the CNS was significantly attenuated by leptin administration as outlined in Leptin regulation of the anorexic response to glucagon-like Peptide-1 receptor stimulation. Diabetes. 2006 Dec;55(12):3387-93
Does increased plasma levels of GLP-1 seen after gastric bypass surgery contribute to the development of weight loss and/or improved glucose control in some subjects? See Gut hormones and Bariatric Surgery for an overview