GLP-1 and energy balance: an integrated model of short-term and long-term control
Open accessAbstract
Glucagon-like peptide 1 (GLP-1), a peptide secreted from the intestine in response to nutrient ingestion, is perhaps best known for its effect on glucose-stimulated insulin secretion. GLP-1 is also secreted from neurons in the caudal brainstem, and it is well-established that, in rodents, central administration of GLP-1 potently reduces food intake. Over the past decade, GLP-1 has emerged not only as an essential component of the system that regulates blood glucose levels but also as a viable therapeutic target for the treatment of type 2 diabetes mellitus. However, although GLP-1 receptor agonists are known to produce modest but statistically significant weight loss in patients with diabetes mellitus, our knowledge of how endogenous GLP-1 regulates food intake and body weight remains limited. The purpose of this Review is to discuss the evolution of our understanding of how endogenous GLP-1 modulates energy balance. Specifically, we consider contributions of both central and peripheral GLP-1 and propose an integrated model of short-term and long-term control of energy balance. Finally, we discuss this model with respect to current GLP-1-based therapies and suggest ongoing research in order to maximize the effectiveness of GLP-1-based treatment of obesity.
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Reducing the expression of the proglucagon gene specifically in the nucleus tractus solitarius (NTS) results in heightened appetite and weight gain in rats.
“Conversely, reducing the expression of the proglucagon gene, responsible for encoding GLP-1, specifically in the nucleus tractus solitarius (NTS), results in heightened appetite and weight gain in rats.11”
From GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review (2024) · cites this paper as [11]
The “Central GLP-1 and energy balance” section (page unavailable) reports that reducing GCG expression in the caudal nucleus of the solitary tract in rats caused hyperphagia and increased fat accumulation in response to a high-fat diet. It attributes weight gain to a different intervention—chronic central GLP-1 receptor blockade—so it does not establish weight gain from the NTS gene-expression reduction itself. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn rats, administering the GLP-1 receptor antagonist exendin (9-39) directly into the brain increases food consumption in satiated rats.
“These studies demonstrate that administering the GLP-1 receptor antagonist exendin (9–39) directly into the brain increases food consumption in satiated rats.”
From GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review (2024) · cites this paper as [11]
The Central GLP-1 and energy balance section (page unavailable) reports that chronic intracerebroventricular administration of exendin 9 caused hyperphagia in rats, supporting the brain-administration and increased-consumption parts of the claim. It does not specify that the rats were satiated; the satiation-related findings in the Peripheral GLP-1 and energy balance section concern intraperitoneal administration. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGLP-1 has a central anorexigenic effect.
“GLP-1 has a central anorexigenic effect.”
From GLP-1 single, dual, and triple receptor agonists for treating type 2 diabetes and obesity: a narrative review (2024) · cites this paper as [11]
GLP-1RAs promote glucose-dependent insulin secretion, suppress glucagon release, and delay gastric emptying, thereby attenuating postprandial glucose excursions.
“These agents promote glucose-dependent insulin secretion, suppress glucagon release, and delay gastric emptying,29 thereby attenuating postprandial glucose excursions.30”
From Metabolic rebound after GLP-1 receptor agonist discontinuation: a systematic review and meta-analysis (2025) · cites this paper as [30]
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References 120 · Cited by 220
Research works printed but not linked: 2
- [35]Sandoval DA Bagnol D Woods SC D’Alessio DA Seeley RJ Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake Diabetes 57 2046 2054 2008 18487451 PMC2494674
- [100]Flint A Raben A Astrup A Holst JJ Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans J Clin Invest 101 515 520 1998 9449682 PMC508592
- Authors
- Barrera, J. G., Sandoval, D. A., D'Alessio, D. A., & Seeley, R. J.
- Affiliations
- University of Cincinnati (US)
- Corresponding author
- Seeley, Randy J.
- Venue
- Nature Reviews Endocrinology
- Published
- 2011-06-07
- Volume
- 7
- Issue
- 9
- Pages
- 507-516
- ISSN
- 1759-5029 (ISSN-L)
- 1759-5037
- PMC
- PMC4231434
- OpenAlex
- W2146849752
- Cited by
- 220
- References
- 120
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 12 · 2023: 10 · 2022: 13 · 2021: 10 · 2020: 16 · 2019: 5 · 2018: 18 · 2017: 16 · 2016: 19 · 2015: 15 · 2014: 19 · 2013: 22 · 2012: 20
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000077)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082480)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- glucagon-like peptide-1, energy balance, food intake regulation, obesity, GLP-1 receptor agonists, type 2 diabetes, glucose-stimulated insulin secretion, body weight regulation
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Eating, Energy Metabolism, Humans, Hypoglycemic Agents, Insulin, Receptors, Glucagon, Glucagon-Like Peptide 1
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