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.
Secher et al. applied multiple techniques, including region-specific injections of GLP-1R antagonists, lesioning specific nerves and nuclei, ex vivo electrophysiological studies, and peripheral administration of a fluorescently-labeled liraglutide molecule in rats, WT mice, and Glp1r-/- mice, to dissect mechanisms that link peripheral administration of a GLP-1R agonist to reduced food intake and weight loss. Although liraglutide was taken up by all circumventricular organs as well as the ARC and PVN in the hypothalamus, Secher et al determined that it is the pro-opiomelanocortin/cocaine- and amphetamine-regulated transcript (POMC/CART) neurons in the ARC that are the direct targets of liraglutide-induced weight loss, whereas the NTS, AP, PVN and vagus nerve are not involved. Indeed, GLP-1R blockade by direct injection of exendin(9-39) into the ARC abolished the weight loss effects of liraglutide, whereas neither injection of exendin(9-39) into or electrolytic lesion of the PVN impacted the ability of liraglutide to reduce weight gain in rats. Remarkably, peripheral administration of fluorescently-labeled liraglutide led to internalization of the peptide by anorexigenic POMC/CART neurons in the ARC. Secher et al. revealed that GLP-1R itself is important for mediating the uptake of uptake of fluorescently-labeled liraglutide into the CNS, as peripheral administration of the peptide failed to accumulate within the CNS of mice with a global knockout of Glp1r. In contrast, no uptake of peripherally-administered liraglutide was detected in the NTS of WT mice. Liraglutide also acted indirectly, via GABAergic neurons, to inhibit the activity of orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons in the ARC The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss J Clin Invest. doi:10.1172/JCI75276 and summarized in Glucagon-like peptide-1 receptors in the brain: controlling food intake and body weight J. Clin Invest 2014 Oct;124(10):4223-6.
Sisley et al used mouse genetics to disrupt the GLP-1R using either Nestin-Cre or Phox2B Cre to disrupt central or peripheral nervous system GLP-1R circuits. Although nodose Glp1r expression was markedly reduced by Phox2b-driven recombination, the basal phenotype (glucose/body weight) or the response to liraglutide was not impaired. Mice with nestin-Cre-driven inactivation of the Glp1r had no basal phenotype with respect to glucose homeostasis or body weight, however the anorectic effect of liraglutide was attenuated, implicating a role for central GLP-1Rs within the nestin expression domain as contributing to GLP-1R circuits controlling pharmacological GLP-1R-dependent food intake. Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect 2014 Jun 2; 124(6): 2456–2463.
To more precisely map the putative hypothalamic GLP-1R nuclei and circuits Burmeister and colleagues used several different Cre driver lines to reduce GLP-1R expression within the hypothalamus. Nkx2.1-Cre was used to knockdown Glp1r broadly within the hypothalamus, whereas Sim1-Cre and POMC-Cre were used to target GLP-1R within the PVN and POMC neurons. Remarkably, none of these mice exhibited marked basal phenotypes, nor did they exhibit marked attenuation to the exogenous actions of GLP-1R agonists on food intake or body weight. These findings illustrate the tremendous redundancy of CNS circuits mediating the anorectic GLP-1 response in mice, and imply other regions, such as the hindbrain, are critically important. The Hypothalamic Glucagon-Like Peptide-1 (GLP-1) Receptor (GLP-1R) is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice Diabetes. 2016 Dec 1. pii: db161102.
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].
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
Shirazi and colleagues demonstrated that icv exendin-4 robustly increased IL-6 expression in the rat hypothalamus, with increased pSTAT expression in the hypothalamus and DVC and increased POMC expression in the hypothalamus and hindbrain. Smaller but detectable increases in IL-1b were also observed. Administration of IL-6 antisera or an IL-1R antagonist attenuated the exendin-4-mediated reduction of food intake and weight loss over a 22 h period. Similarly, the anorectic actions of Ex-4 over a 24h period were blunted in IL-1R-/- mice and in mice with a brain-specific knockdown of IL-6. Furthermore, combined genetic knockdown of both IL-6 and IL-1b attenuated the acute hypothermic response to Ex-4. Hence, a subset of cytokines links GLP-1R signaling to acute control of food intake and body weight in rats and mice Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6 Proc Natl Acad Sci U S A. 2013 Sep 18.
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.
Hayes and colleagues examined CNS mechanisms linking GLP-1R activation in the hindbrain to control of food intake. 4th ventricle Icv exendin-4 transiently activated PKA activity and p44/42 MAPK phosphorylation and reduced AMPKa2 phosphorylation in the dorsal vagal complex, and the Ex-4-mediated reduction in food intake was blocked by the inhibitor RpcAMP. Pre-treatment with U0126 reversed the inhibitory effect of Ex-4 on food intake (predominantly meal number, not meal size) whereas activation of AMPK activity with AICAR attenuated the suppressive effect of Ex-4 on food intake by 50%. Conversely, intraperitoneal Ex-4 suppressed food intake via reduction in meal size. The inhibitory effects of Ex-4 on MAPK and AMPK were partially PKA-dependent. The site of action of Ex-4 was further localized by intraparenchymal injections, to the medial NTS GLP-1R system. See Intracellular Signals Mediating the Food Intake-Suppressive Effects of Hindbrain Glucagon-like Peptide-1 Receptor Activation Cell Metab. 2011 Mar 2;13(3):320-30
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
Paradoxically, despite the effects of ICV GLP-1 on 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.
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
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.
Beiroa and colleagues demonstrated that icv administration of GLP-1R agonists in mice produced relatively greater weight loss than that achieved through peripheral administration, due to preferential activation of CNS circuits controlling energy expenditure. Liraglutide given icv increased BAT temperature and induced a gene and protein expression profile favoring thermogenesis. Icv liraglutide also induced browning in WAT depots. The VMH was most sensitive to the central thermogenic actions of liraglutide, which reduced VMH pAMPK. ICV AICAR or adenoviral AMPK expression blunted the ability of liraglutide to increase BAT activity. In contrast to results of other human studies (see below), exenatide and liraglutide treatment of obese human diabetic subjects for 1 year exhibited a reduction in BMI, resting energy expenditure was higher in these subjects compared to metformin-treated controls (after adjustment to fat free mass). GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK Diabetes June 10, 2014, doi:10.2337/db14-030
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
The effects of GLP-1 and PYY, administered separately, or together, on food intake and brain activity, was assessed in healthy normal weight human subjects using functional MRI. Both GLP-1 and PYY alone reduced energy intake in fasted subjects presented with a buffet lunch, and the combination of both hormones produced an additive and significantly greater reduction in energy intake. Viewing of food intake images in the fasted state produced activation of Blood Oxygen Level Dependent (BOLD) MRI signals (assessed in food sensitive areas; amygdala, caudate, putamen, insula, nucleus acumbens, orbitofrontal cortex, and putamen). Although no significant changes were observed in the absence of food with hormone infusion, PYY alone, or PYY plus GLP-1 reduced the extent of BOLD fMRI signals generated with feeding. The Gut Hormones PYY(3-36) and GLP-1(7-36 amide) Reduce Food Intake and Modulate Brain Activity in Appetite Centers in Humans Cell Metab. 2011 Oct 11
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]
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? The majority of evidence suggests that GLP-1R activation in obese/diabetic humans produces weight loss through reduction of appetite, and not through induction of energy expenditure.
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
van Can and colleagues examined the effects of liraglutide, 1.8 and 3 mg daily, on glucose homeostasis, gastric emptying, appetite, and energy expenditure, in non-diabetic obese male and female subjects, mean age 47, mean weight 102 kg. Gastric emptying assessed over 5 hrs was not significantly different for liraglutide vs. placebo, however liraglutide reduced the rate of gastric emptying during the first hour after the test meal, most evident with the 3 mg dose. Both energy intake and energy expenditure and RQ (consistent with more fat oxidation) were lower in subjects treated with liraglutide. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite, and energy metabolism in obese, non-diabetic adults Int J Obes (Lond). 2013 Sep 3. doi: 10.1038/ijo.2013.162
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