GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial
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Aims/hypothesis Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome).Methods In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center.Results Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation.Conclusions/interpretation For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.Trial registration ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.
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When GLP-1 binds to its receptors in the hypothalamus, it activates POMC/CART neurons that promote satiety and inhibits NPY/AgRP neurons that induce hunger, thereby enhancing fullness and reducing food intake.
“When GLP-1 binds to its receptors in the hypothalamus, it activates specific neurons, including those that promote satiety (POMC/CART neurons) and inhibits those that induce hunger (NPY/AgRP neurons), thereby enhancing the feeling of fullness and reducing food intake.233,267”
From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [267]
The Results section reports GLP-1 receptors on neurons in human hypothalamic nuclei, and the Introduction and Discussion describe a possible role for brain GLP-1 signalling in satiety and reduced food intake (page numbers unavailable). The paper does not identify those neurons as POMC/CART or NPY/AgRP, or show that GLP-1 activates one group and inhibits the other. It presents hypothalamic effects on appetite as a possibility, not the demonstrated mechanism stated in the claim. (LLM, conf=0.86)
Experimental — accuracy not yet measuredNausea (25.0%), vomiting (12.2%), diarrhea (11.6%), constipation (11.0%), and dyspepsia (6.4%) were frequently reported with liraglutide and were tolerated by most patients over time.
“Nausea (25.0%), vomiting (12.2%), diarrhea (11.6%), constipation (11.0%), and dyspepsia (6.4%) were frequently reported, which were tolerated by most patients over time [48–50].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [50]
Liraglutide (Victoza) is a GLP-1 agonist approved in 2010 for type 2 diabetes, with a recommended dose of 1.8 mg daily subcutaneously.
“Liraglutide (Victoza®) is a glucagon-like peptide 1 (GLP-1) agonist that was approved in 2010 for the treatment of T2DM; the recommended dose is subcutaneous (SC) administration of 1.8 mg daily [50].”
From Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? (2021) · cites this paper as [50]
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Do GLP-1 Receptor Agonists Alter Brain Responses to Reward-Related Cues? A Systematic Review
Dang, V., Sambuco, N., Yammine, L., & Versace, F. (2026) · doi:10.64898/2026.01.31.702984 · Cited by 4 · see citing works
- Authors
- Farr, O. M., Sofopoulos, M., Tsoukas, M. A., Dincer, F., Thakkar, B., Sahin-Efe, A., Filippaios, A., Bowers, J., Srnka, A., Gavrieli, A., Ko, B.-J., Liakou, C., Kanyuch, N., Tseleni-Balafouta, S., & Mantzoros, C. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- St Savas Hospital (GR)
- Corresponding author
- Farr, Olivia M.
- ORCID
- Venue
- Diabetologia
- Published
- 2016-02-01
- Volume
- 59
- Issue
- 5
- Pages
- 954-965
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC4826792
- OpenAlex
- W2255282938
- Cited by
- 287
- References
- 42
- Citations by year
- 2026: 36 · 2025: 46 · 2024: 24 · 2023: 30 · 2022: 25 · 2021: 30 · 2020: 18 · 2019: 22 · 2018: 24 · 2017: 21 · 2016: 11
- FWCI
- 16.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Novo Nordisk
- NIH Clinical Center (UL1 RR025758)
- 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
- GLP-1 receptor, liraglutide, type 2 diabetes, food cues, parietal cortex, hypothalamus, medulla oblongata, brain activation, nausea, reward systems, insula, putamen, weight loss, GLP-1 analogues, neuroimaging, neurocognitive function, immunohistochemistry
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Adult, Aged, Aged, 80 and over, Blood Glucose, Brain, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Humans, Hypoglycemic Agents, Hypothalamus, Magnetic Resonance Imaging, Male, Medulla Oblongata, Middle Aged, Cross-Over Studies, Glucagon-Like Peptide 1
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