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Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons – Implications for energy balance and glucose control
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OBJECTIVE: The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, liraglutide, stimulates insulin secretion and efficiently suppresses food intake to reduce body weight. As such, liraglutide is growing in popularity in the treatment of diabetes and chronic weight management. Within the brain, liraglutide has been shown to alter the activity of hypothalamic proopiomelanocortin (POMC) and Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons. Moreover, the acute activities of POMC and NPY neurons have been directly linked to feeding behavior, body weight, and glucose metabolism. Despite the increased usage of liraglutide and other GLP-1 analogues as diabetic and obesity interventions, the cellular mechanisms by which liraglutide alters the activity of metabolically relevant neuronal populations are poorly understood. METHODS: In order to resolve this issue, we utilized neuron-specific transgenic mouse models to identify POMC and NPY neurons for patch-clamp electrophysiology experiments. RESULTS: receptors and enhanced activity of pre-synaptic GABAergic neurons, which required both TrpC5 subunits and K-ATP channels. In support of an additive role of leptin and liraglutide in suppressing food intake, leptin potentiated the acute effects of liraglutide to activate POMC neurons. TrpC5 subunits in POMC neurons were also required for the intact pharmacological effects of liraglutide on food intake and body weight. Thus, the current study adds to recent work from our group and others, which highlight potential mechanisms to amplify the effects of GLP-1 agonists in vivo. Moreover, these data highlight multiple sites of action (both pre- and post-synaptic) for GLP-1 agonists on this circuit. CONCLUSIONS: Taken together, our results identify critical molecular mechanisms linking GLP-1 analogues in arcuate POMC and NPY/AgRP neurons with metabolism.
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“GLP-1 and GLP-1RAs inhibit ARCNPY/AgRP neurons through upstream presynaptic g-aminobutyric acid–releasing (GABAergic) neurons (13, 14).”
From GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans (2024) · cites this paper as [14]
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Quarta, C., Claret, M., Zeltser, L. M., Williams, K. W., Yeo, G. S. H., Tschöp, M. H., Diano, S., Brüning, J. C., & Cota, D. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00345-3 · Cited by 194
Self-citationAgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity
Vohra, M. S., Benchoula, K., Serpell, C. J., & Wong, E. H. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174611 · Cited by 199
Metadata
- Authors
- He, Z., Gao, Y., Lieu, L., Afrin, S., Cao, J., Michael, N. J., Dong, Y., Sun, J., Guo, H., & Williams, K. W.
- Affiliations
- Zhujiang Hospital (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- The University of Texas Southwestern Medical Center (US)
- Guangzhou University of Chinese Medicine (CN)
- Corresponding author
- Guo, Hongbo
- Williams, Kevin W.
- ORCID
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 28
- Pages
- 120-134
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC6822260
- OpenAlex
- W2965632554
- Cited by
- 128
- References
- 86
- Citations by year
- 2026: 17 · 2025: 28 · 2024: 26 · 2023: 18 · 2022: 16 · 2021: 17 · 2020: 6
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Guangdong Provincial Clinical Medical Centre for Neurosurgery (2013B020400005)
- 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 › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- liraglutide, GLP-1 receptor agonists, POMC neurons, NPY/AgRP neurons, hypothalamus, arcuate nucleus, dietary intake, body weight, leptin, ATP-sensitive potassium channels, GABAergic neurons, energy balance, glucose metabolism, obesity, diabetes mellitus
- MeSH terms
- Liraglutide, Animals, Blood Glucose, Energy Metabolism, Hypoglycemic Agents, Hypothalamus, Male, Mice, Transgenic, Neurons, Neuropeptide Y, Pro-Opiomelanocortin, Mice, Agouti-Related Protein
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