Endogenous Glucagon-like Peptide-1 Suppresses High-Fat Food Intake by Reducing Synaptic Drive onto Mesolimbic Dopamine Neurons

Glucagon-like peptide-1 receptor (GLP-1R) activation in the ventral tegmental area (VTA) is physiologically relevant for the control of palatable food intake. Here, we tested whether the food intake-suppressive effects of VTA GLP-1R activation are mediated by glutamatergic signaling within the VTA. Intra-VTA injections of the GLP-1R agonist exendin-4 (Ex-4) reduced palatable high-fat food intake in rats primarily by reducing meal size; these effects were mediated in part via glutamatergic AMPA/kainate but not NMDA receptor signaling. Additional behavioral data indicated that GLP-1R expressed specifically within the VTA can partially mediate the intake- and body weight-suppressive effects of systemically administered Ex-4, offering the intriguing possibility that this receptor population may be clinically relevant for food intake control. Intra-VTA Ex-4 rapidly increased tyrosine hydroxylase levels within the VTA, suggesting that GLP-1R activation modulates VTA dopaminergic signaling. Further evidence for this hypothesis was provided by electrophysiological data showing that Ex-4 increased the frequency of AMPA-mediated currents and reduced the paired/pulse ratio in VTA dopamine neurons. Together, these data provide novel mechanisms by which GLP-1R agonists in the mesolimbic reward system control for palatable food intake.

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High-fat diet effects on gut motility, hormone, and appetite responses to duodenal lipid in healthy men

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00375.2002 ◽

2003 ◽

Vol 284 (2) ◽

pp. G188-G196 ◽

Cited By ~ 73

Author(s):

K. A. Boyd ◽

D. G. O'Donovan ◽

S. Doran ◽

J. Wishart ◽

I. M. Chapman ◽

...

Keyword(s):

Food Intake ◽

High Fat Diet ◽

Crossover Fashion ◽

Plasma Glucagon ◽

Acute Effects ◽

High Fat ◽

Lipid Infusion ◽

Healthy Men ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

There is evidence that gastrointestinal function adapts in response to a high-fat (HF) diet. This study investigated the hypothesis that an HF diet modifies the acute effects of duodenal lipid on appetite, antropyloroduodenal pressures, plasma CCK and plasma glucagon-like peptide-1 (GLP-1) levels in humans. Twelve healthy men were studied twice in randomized, crossover fashion. The effects of a 90-min duodenal lipid infusion (6.3 kJ/min) on the above parameters were assessed immediately following 14-day periods on either an HF or a low-fat (LF) diet. After the HF diet, pyloric tonic and phasic pressures were attenuated, and the number of antropyloroduodenal pressure-wave sequences was increased when compared with the LF diet. Plasma CCK and GLP-1 levels did not differ between the two diets. Hunger was greater during the lipid infusion following the HF diet, but there was no difference in food intake. Therefore, exposure to an HF diet for 14 days attenuates the effects of duodenal lipid on antropyloroduodenal pressures and hunger without affecting food intake or plasma hormone levels.

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Combination of α-Glycosyl-Isoquercitrin and Soybean Fiber Promotes Quercetin Bioavailability and Glucagon-like Peptide-1 Secretion and Improves Glucose Homeostasis in Rats Fed a High-Fat High-Sucrose Diet

Journal of Agricultural and Food Chemistry ◽

10.1021/acs.jafc.1c01388 ◽

2021 ◽

Author(s):

Aphichat Trakooncharoenvit ◽

Hiroshi Hara ◽

Tohru Hira

Keyword(s):

Glucose Homeostasis ◽

High Fat ◽

Sucrose Diet ◽

High Sucrose Diet ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

High Sucrose

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Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00446.2012 ◽

2013 ◽

Vol 304 (7) ◽

pp. E677-E685 ◽

Cited By ~ 34

Author(s):

Melissa A. Burmeister ◽

Jennifer Ayala ◽

Daniel J. Drucker ◽

Julio E. Ayala

Keyword(s):

Food Intake ◽

Glucose Metabolism ◽

Dependent Manner ◽

Anorectic Effect ◽

Dependent Inhibition ◽

Glycolytic Inhibitor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Amp Activated Protein Kinase ◽

Mediated Reduction

Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.

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Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00243.2015 ◽

2016 ◽

Vol 310 (10) ◽

pp. R906-R916 ◽

Cited By ~ 9

Author(s):

Alison D. Kreisler ◽

Linda Rinaman

Keyword(s):

Food Intake ◽

Potential Role ◽

Liquid Diet ◽

Neural Activation ◽

Intracerebroventricular Injection ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Diet Intake ◽

Published Research ◽

Diet Type

Published research supports a role for central glucagon-like peptide 1 (GLP-1) signaling in suppressing food intake in rodent species. However, it is unclear whether GLP-1 neurons track food intake and contribute to satiety, and/or whether GLP-1 signaling contributes to stress-induced hypophagia. To examine whether GLP-1 neurons track intake volume, rats were trained to consume liquid diet (LD) for 1 h daily until baseline intake stabilized. On test day, schedule-fed rats consumed unrestricted or limited volumes of LD or unrestricted volumes of diluted (calorically matched to LD) or undiluted Ensure. Rats were perfused after the test meal, and brains processed for immunolocalization of cFos and GLP-1. The large majority of GLP-1 neurons expressed cFos in rats that consumed satiating volumes, regardless of diet type, with GLP-1 activation proportional to intake volume. Since GLP-1 signaling may limit intake only when such large proportions of GLP-1 neurons are activated, a second experiment examined the effect of central GLP-1 receptor (R) antagonism on 2 h intake in schedule-fed rats. Compared with baseline, intracerebroventricular vehicle (saline) suppressed Ensure intake by ∼11%. Conversely, intracerebroventricular injection of vehicle containing GLP-1R antagonist increased intake by ∼14% compared with baseline, partly due to larger second meals. We conclude that GLP-1 neural activation effectively tracks liquid diet intake, that intracerebroventricular injection suppresses intake, and that central GLP-1 signaling contributes to this hypophagic effect. GLP-1 signaling also may contribute to satiety after large volumes have been consumed, but this potential role is difficult to separate from a role in the hypophagic response to intracerebroventricular injection.

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High-fat diet alters fluid intake without reducing sensitivity to glucagon-like peptide-1 receptor agonist effects

Physiology & Behavior ◽

10.1016/j.physbeh.2020.112910 ◽

2020 ◽

Vol 221 ◽

pp. 112910

Author(s):

K Linnea Volcko ◽

Quinn E Carroll ◽

Destiny J Brakey ◽

Derek Daniels

Keyword(s):

High Fat Diet ◽

Receptor Agonist ◽

Fluid Intake ◽

High Fat ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00356.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. R1479-R1485 ◽

Cited By ~ 55

Author(s):

Matthew R. Hayes ◽

Scott E. Kanoski ◽

Bart C. De Jonghe ◽

Theresa M. Leichner ◽

Amber L. Alhadeff ◽

...

Keyword(s):

Food Intake ◽

Vagal Afferents ◽

Oral Glucose ◽

Afferent Fibers ◽

The Common ◽

Vagal Afferent ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

And Control ◽

Hepatic Branch

The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9–39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7–36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.

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Do the Actions of Glucagon-Like Peptide-1 on Gastric Emptying, Appetite, and Food Intake Involve Release of Amylin in Humans?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2133 ◽

2010 ◽

Vol 95 (5) ◽

pp. 2367-2375 ◽

Cited By ~ 23

Author(s):

Meena Asmar ◽

Michael Bache ◽

Filip K. Knop ◽

Sten Madsbad ◽

Jens J. Holst

Keyword(s):

Gastric Emptying ◽

Food Intake ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery

International Journal of Obesity ◽

10.1038/ijo.2016.121 ◽

2016 ◽

Vol 40 (11) ◽

pp. 1699-1706 ◽

Cited By ~ 83

Author(s):

M S Svane ◽

N B Jørgensen ◽

K N Bojsen-Møller ◽

C Dirksen ◽

S Nielsen ◽

...

Keyword(s):

Gastric Bypass ◽

Food Intake ◽

Bypass Surgery ◽

Peptide Yy ◽

Gastric Bypass Surgery ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Appetite hormones and addiction

10.1093/med/9780198797746.003.0012 ◽

2018 ◽

Author(s):

David J. Nutt ◽

Liam J. Nestor

Keyword(s):

Eating Disorder ◽

Food Intake ◽

Food Consumption ◽

Neural Substrates ◽

Reward Sensitivity ◽

Substance Addiction ◽

Alcohol And Drugs ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Brain

Many of the same behavioural and brain disturbances observed in addiction are also seen in obesity and binge-eating disorder. This suggests that there are shared neural substrates between substance addiction and compulsive food consumption. Food intake and appetite are regulated by numerous appetite hormones that exert their effects through brain systems involved in reward sensitivity, stress, impulsivity, and compulsivity. There is now emerging evidence that appetite hormones (e.g. ghrelin, glucagon-like peptide-1, orexin) can modulate addictive behaviours (e.g. craving) and the intake of alcohol and drugs. Therefore, there is an emerging shift into a new field of testing drugs that affect appetite hormones and their receptors in the brain, and their use in regulating the brain mechanisms that lead to relapse in addiction disorders.

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