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Park JS, Kim KS, Choi HJ. Glucagon-Like Peptide-1 and Hypothalamic Regulation of Satiation: Cognitive and Neural Insights from Human and Animal Studies. Diabetes Metab J 2025; 49:333-347. [PMID: 40367985 DOI: 10.4093/dmj.2025.0106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 04/16/2025] [Indexed: 05/16/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as blockbuster drugs for treating metabolic diseases. Glucagon-like peptide-1 (GLP-1) plays a pivotal role in glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and acting on the central nervous system to regulate satiation and satiety. This review summarizes the discovery of GLP-1 and the development of GLP-1RAs, with a particular focus on their central mechanisms of action. Human neuroimaging studies demonstrate that GLP-1RAs influence brain activity during food cognition, supporting a role in pre-ingestive satiation. Animal studies on hypothalamic feed-forward regulation of hunger suggest that cognitive hypothalamic mechanisms may also contribute to satiation control. We highlight the brain mechanisms of GLP-1RA-induced satiation and satiety, including cognitive impacts, with an emphasis on animal studies of hypothalamic glucagon-like peptide-1 receptor (GLP-1R) and GLP-1R-expressing neurons. Actions in non-hypothalamic regions are also discussed. Additionally, we review emerging combination drugs and oral GLP-1RA formulations aimed at improving efficacy and patient adherence. In conclusion, the dorsomedial hypothalamus (DMH)-a key GLP-1RA target-mediates pre-ingestive cognitive satiation, while other hypothalamic GLP-1R neurons regulate diverse aspects of feeding behavior, offering potential therapeutic targets for obesity treatment.
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Affiliation(s)
- Joon Seok Park
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Kyu Sik Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung Jin Choi
- Department of Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
- Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul, Korea
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Korea
- Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea
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Farokhnia M, Tazare J, Pince CL, Bruns N, Gray JC, Lo Re V, Fiellin DA, Kranzler HR, Koob GF, Justice AC, Vendruscolo LF, Rentsch CT, Leggio L. Glucagon-like peptide-1 receptor agonists, but not dipeptidyl peptidase-4 inhibitors, reduce alcohol intake. J Clin Invest 2025; 135:e188314. [PMID: 40048376 PMCID: PMC12043080 DOI: 10.1172/jci188314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/27/2025] [Indexed: 03/30/2025] Open
Abstract
BACKGROUNDDespite growing preclinical evidence that glucagon-like peptide1 receptor agonists (GLP-1RAs) could be repurposed to treat alcohol use disorder (AUD), clinical evidence is scarce. Additionally, the potential impact of dipeptidyl peptidase-4 inhibitors (DPP-4Is) on alcohol intake is largely unknown.METHODSWe conducted a large cohort study using 2008-2023 electronic health records data from the U.S. Department of Veterans Affairs. Changes in Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores were compared between propensity-score-matched GLP-1RA recipients, DPP-4I recipients, and unexposed comparators. We further tested the effects of 2 DPP-4Is, linagliptin and omarigliptin, on binge-like alcohol drinking in mice and operant oral alcohol self administration in alcohol-dependent rats, models previously used to show a significant effect of the GLP-1RA semaglutide in reducing alcohol intake.RESULTSGLP-1RA recipients reported a greater reduction in AUDIT-C scores than unexposed individuals (difference-in-difference [DiD]: 0.09 [95% CI: 0.03, 0.14], P = 0.0025) and DPP-4I recipients (DiD: 0.11 [95% CI: 0.05,0.17], P = 0.0002). Reductions in drinking were more pronounced among individuals with baseline AUD (GLP-1RA versus unexposed: 0.51 [95% CI: 0.29,0.72], P < 0.0001; GLP-1RA versus DPP-4I: 0.65 [95% CI: 0.43,0.88], P < 0.0001) and baseline hazardous drinking (GLP-1RA versus unexposed: 1.38 [95% CI: 1.07,1.69], P < 0.0001; GLP-1RA versus DPP-4I: 1.00 [95% CI: 0.68,1.33], P < 0.0001). There were no differences between DPP-4I recipients and unexposed individuals. The latter results were confirmed via a reverse translational approach. Specifically, neither linagliptin nor omarigliptin reduced alcohol drinking in mice or rats. The rodent experiments also confirmed target engagemhent, as both DPP-4Is reduced blood glucose levels.CONCLUSIONConvergent findings across humans, mice, and rats indicated that GLP-1RAs, but not DPP-4Is, reduce alcohol consumption and may be efficacious in treating AUD.FUNDINGThis work was supported by the National Institutes of Health Intramural Research Program (ZIA DA000635, ZIA DA000644, ZIA DA000602), National Institute on Alcohol Abuse and Alcoholism extramural funding (R01 AA030041, P01 AA029545, U01 AA026224, U24 AA020794, U01 AA020790, U10 AA013566), the U.S. Department of Veterans Affairs (I01BX004820), and an Alkermes Pathways Research Award.
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Affiliation(s)
- Mehdi Farokhnia
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - John Tazare
- Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Claire L. Pince
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, NIH, Baltimore, Maryland, USA
- Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore, Maryland, USA
| | - Nicolaus Bruns
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, NIH, Baltimore, Maryland, USA
- Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore, Maryland, USA
| | - Joshua C. Gray
- Department of Medical and Clinical Psychology, Uniformed Services University, Bethesda, Maryland, USA
| | - Vincent Lo Re
- Division of Infectious Diseases, Department of Medicine and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - David A. Fiellin
- Program in Addiction Medicine and
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - Henry R. Kranzler
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Mental Illness Research, Education, and Clinical Center, Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - George F. Koob
- Neurobiology of Addiction Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, NIH, Baltimore, Maryland, USA
| | - Amy C. Justice
- Program in Addiction Medicine and
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, Department of Veterans Affairs, West Haven, Connecticut, USA
| | - Leandro F. Vendruscolo
- Stress & Addiction Neuroscience Unit, Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore, Maryland, USA
| | - Christopher T. Rentsch
- Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA
- VA Connecticut Healthcare System, Department of Veterans Affairs, West Haven, Connecticut, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA
- Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA
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Edvardsson CE, Cadeddu D, Ericson M, Adermark L, Jerlhag E. An inhibitory GLP-1 circuit in the lateral septum modulates reward processing and alcohol intake in rodents. EBioMedicine 2025; 115:105684. [PMID: 40245495 PMCID: PMC12044336 DOI: 10.1016/j.ebiom.2025.105684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/24/2025] [Accepted: 03/20/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Alcohol use disorder (AUD) is a complex psychiatric condition with limited effective treatment options. Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as potential AUD treatment, as they have been shown to modulate reward-related behaviours, including those linked to alcohol consumption. However, the underlying mechanisms and neurocircuitry remain unclear. This study investigated the role of GLP-1R in the lateral septum (LS), a brain region highly expressing GLP-1R and implicated in reward-related behaviours, including alcohol-induced reward and consumption. METHODS Behavioural, neurochemical, molecular, and electrophysiological methods were used to investigate the effect of LS GLP-1R signalling in alcohol-mediated responses in rodents. FINDINGS LS GLP-1R activation attenuated alcohol's rewarding effects, reducing locomotor stimulation, place preference, and accumbal dopamine release. Intra-LS infusion of the GLP-1R agonist exendin-4 (Ex4) reduced alcohol intake dose-dependently without affecting food or water consumption, while GLP-1R inhibition increased alcohol intake. Furthermore, LS GLP-1R expression correlated with alcohol intake in male but not female rats, suggesting sex-specific effects of long-term alcohol exposure. Ex vivo electrophysiology indicated that GLP-1R activation depressed LS neurotransmission via a gamma-aminobutyric acid (GABA)A receptor-dependent mechanism. INTERPRETATION This study provides new insights into how GLP-1R agonists may reduce alcohol intake. Overall, the findings underscore the potentially inhibitory neuromodulatory role of LS GLP-1R in regulating alcohol consumption through the modulation of dopaminergic reward processes tentatively involving GABA transmission. FUNDING Swedish Research Council (2023-2600), Sahlgrenska University HospitalLUA/ALF (grant no. 723941), Adlerbertska Research Foundation and Professor Bror Gadelius Foundation.
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Affiliation(s)
- Christian E Edvardsson
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Davide Cadeddu
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Mia Ericson
- Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Louise Adermark
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Addiction Biology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Elisabet Jerlhag
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Liu WH, Liu C, Xue Y, Sun XR, Chen XY, Chen L. Activation of GLP-1R modulates the spontaneous discharge of nigral dopaminergic neurons and motor behavior in mice with chronic MPTP Parkinson's disease. Front Aging Neurosci 2025; 17:1529919. [PMID: 40353061 PMCID: PMC12062123 DOI: 10.3389/fnagi.2025.1529919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 04/07/2025] [Indexed: 05/14/2025] Open
Abstract
The gradual decline of nigral dopaminergic neurons is the main cause of Parkinson's disease (PD), yet as of now, there exists no conclusive therapeutic intervention. Glucagon-like peptide-1 (GLP-1) is an incretin, which is also a key substance regulating neuronal activity and synaptic transmission. GLP-1 receptors (GLP-1Rs) are widely expressed in the central nervous system. Chronic administration of low doses of 1-methyl-4-phenyl, 1,2,3,6-tetrahydropiridine (MPTP) mitigates mortality in mice during the modeling phase, thereby more closely mirroring the progression of PD. This study aims to observe the effects of GLP-1 receptor agonists (GLP-1RAs) on the firing activity of nigral dopaminergic neurons and motor behaviors in MPTP-induced chronic PD mice. Our findings revealed that peripheral administration of GLP-1RAs exendin-4 significantly alleviated motor impairments in MPTP-induced chronic PD mice. Concurrently, peripheral administration of exendin-4 increased the number of active dopaminergic neurons, improved the spontaneous firing activity, as well as alleviated MPTP-induced dopaminergic neuron loss in MPTP-induced PD mice. Furthermore, local administration of exendin-4 directly increased the firing rate of nigral dopaminergic neurons via GLP-1Rs, suggesting that peripheral administration of exendin-4 may exert neuroprotection through its mild excitation on dopaminergic neurons. These findings collectively imply that peripheral administration of GLP-1RAs may hold potential in the treatment of PD.
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Affiliation(s)
- Wen-Hong Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Cui Liu
- Department of Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical, Jinan, China
| | - Yan Xue
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiang-Rong Sun
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xin-Yi Chen
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Chen
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
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Xu Z, Wen S, Dong M, Zhou L. Targeting central pathway of Glucose-Dependent Insulinotropic Polypeptide, Glucagon and Glucagon-like Peptide-1 for metabolic regulation in obesity and type 2 diabetes. Diabetes Obes Metab 2025; 27:1660-1675. [PMID: 39723473 DOI: 10.1111/dom.16146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 12/09/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024]
Abstract
Obesity and type 2 diabetes are significant public health challenges that greatly impact global well-being. The development of effective therapeutic strategies has become more and more concentrated on the central nervous system and metabolic regulation. The primary pharmaceutical interventions for the treatment of obesity and uncontrolled hyperglycemia are now generally considered to be incretin-based anti-diabetic treatments, particularly glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonists. This is a result of their substantial influence on the central nervous system and the consequent effects on energy balance and glucose regulation. It is increasingly crucial to understand the neural pathways of these pharmaceuticals. The purpose of this review is to compile and present the most recent central pathways regarding glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and glucagon receptors, with a particular emphasis on central metabolic regulation.
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Affiliation(s)
- Zhimin Xu
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, China
| | - Song Wen
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, China
- Fudan Zhangjiang Institute, Fudan University, Shanghai, China
| | - Meiyuan Dong
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, China
| | - Ligang Zhou
- Department of Endocrinology, Shanghai Pudong Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China
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Mostafa MEA, Alrasheed T. Improvement of irritable bowel syndrome with glucagon like peptide-1 receptor agonists: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2025; 16:1548346. [PMID: 40134805 PMCID: PMC11932899 DOI: 10.3389/fendo.2025.1548346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/10/2025] [Indexed: 03/27/2025] Open
Abstract
Introduction Irritable bowel syndrome (IBS) is a severe gastrointestinal condition with symptoms like pain, bloating, diarrhea, and constipation. Glucagon-like peptide-1 (GLP-1) receptors, expressed in the central nervous system and peripheral tissues, have been found to affect gut motility. GLP-1 and its analog ROSE-010 have been shown to inhibit the migrating motor complex and decrease gastrointestinal motility in IBS patients. Aim This systematic review and meta-analysis aim to assess the efficacy and safety of GLP-1 receptor agonists in providing pain and symptom relief for individuals with IBS. Methods The study conducted extensive searches across various databases, including Cochrane Library, Web of Science, PubMed, Google Scholar, and Science Direct, to identify studies on IBS and related drugs. A search strategy using keywords and medical subject heading terms (MeSH) was developed to ensure inclusivity. Exclusion criteria included non-English language studies, books, conference papers, case reports, in vitro studies, animal studies, and non-original articles. Results The study found that ROSE-010 (100 µg) significantly lowered pain intensity in IBS patients compared to a placebo, with an overall odds ratio of 2.30, 95% CI: 1.53-3.46. ROSE-010 (300 µg) is more effective than a placebo for all irritable bowel syndrome subtypes, with consistent effects across trials. ROSE-010 is linked to a greater incidence of nausea, vomiting, and headache than placebo. Conclusion ROSE-010, a glucagon-like peptide-1 receptor agonist, has been shown to reduce pain in individuals with IBS. However, its higher frequency of nausea, vomiting, and headache suggests the need for close monitoring and individualized treatment plans. Further investigation is needed to understand its impact on different IBS subtypes and long-term effects. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024613545.
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Affiliation(s)
- Mohamed E. A. Mostafa
- Department of Anatomy, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Tariq Alrasheed
- Department of Internal Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
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Merkel R, Hernandez NS, Weir V, Zhang Y, Caffrey A, Rich MT, Crist RC, Reiner BC, Schmidt HD. An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking. SCIENCE ADVANCES 2025; 11:eadr5051. [PMID: 40009667 PMCID: PMC11864183 DOI: 10.1126/sciadv.adr5051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 01/28/2025] [Indexed: 02/28/2025]
Abstract
Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate cocaine seeking. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius that project to the ventral tegmental area (VTA) decreased cocaine seeking. Single-nuclei transcriptomics and FISH studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.
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Affiliation(s)
- Riley Merkel
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nicole S. Hernandez
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Vanessa Weir
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Vaegelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Yafang Zhang
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Antonia Caffrey
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthew T. Rich
- Department of Psychiatry, Brain Health Institute, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA
| | - Richard C. Crist
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Benjamin C. Reiner
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Heath D. Schmidt
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Duran M, Willis JR, Dalvi N, Fokakis Z, Virkus SA, Hardaway JA. Integration of Glucagon-Like Peptide 1 Receptor Actions Through the Central Amygdala. Endocrinology 2025; 166:bqaf019. [PMID: 39888375 PMCID: PMC11850305 DOI: 10.1210/endocr/bqaf019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/31/2024] [Accepted: 01/25/2025] [Indexed: 02/01/2025]
Abstract
Understanding the detailed mechanism of action of glucagon-like peptide 1 receptor (GLP-1R) agonists on distinct topographic and genetically defined brain circuits is critical for improving the efficacy and mitigating adverse side effects of these compounds. In this mini-review, we propose that the central nucleus of the amygdala (CeA) is a critical mediator of GLP-1R agonist-driven hypophagia. Here, we review the extant literature demonstrating CeA activation via GLP-1R agonists across multiple species and through multiple routes of administration. The precise role of GLP-1Rs within the CeA is unclear but the site-specific GLP-1Rs may mediate distinct behavioral and physiological hallmarks of GLP-1R agonists on food intake. Thus, we propose important novel directions and methods to test the role of the CeA in mediating GLP-1R actions.
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Affiliation(s)
- Miguel Duran
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jennifer R Willis
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Nilay Dalvi
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Zoe Fokakis
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Sonja A Virkus
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - J Andrew Hardaway
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Klausen MK, Kuzey T, Pedersen JN, Justesen SK, Rasmussen L, Knorr UB, Mason G, Ekstrøm CT, Holst JJ, Koob G, Benveniste H, Volkow ND, Knudsen GM, Vilsbøll T, Fink-Jensen A. Does semaglutide reduce alcohol intake in Danish patients with alcohol use disorder and comorbid obesity? Trial protocol of a randomised, double-blinded, placebo-controlled clinical trial (the SEMALCO trial). BMJ Open 2025; 15:e086454. [PMID: 39779270 PMCID: PMC11749217 DOI: 10.1136/bmjopen-2024-086454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
INTRODUCTION Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies. Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promising effects in reducing alcohol consumption in preclinical experiments, and clinical trials are in high demand to investigate these potentially beneficial effects in patients diagnosed with AUD. METHODS AND ANALYSIS The effects of the once-weekly GLP-1 receptor agonist semaglutide will be investigated in a 26-week, randomised, placebo-controlled, double-blinded clinical trial. 108 patients diagnosed with AUD and comorbid obesity (body mass index (BMI)≥30 kg/m2)) will be randomised to treatment with either semaglutide or placebo in combination with cognitive behavioural therapy. A subgroup of the patients will have structural, functional and neurochemical brain imaging performed at baseline and after 26 weeks of treatment. The primary endpoint is the reduction in heavy drinking days, defined as days with excess consumption of 48/60 g of alcohol per day (women and men, respectively). Secondary endpoints include changes from baseline to week 26 in alcohol consumption, smoking status, quality of life, fibrosis-4 score, plasma concentration of phosphatidylethanol, brain gamma-aminobutyric acid (GABA) levels, alcohol cue reactivity, functional connectivity and white matter tract integrity. STATUS Recruitment started in June 2023. ETHICS AND DISSEMINATION The study is approved by the Ethics Committee of the Capital Region of Denmark, the Danish Board of Health and the Danish Data Protection Agency. All patients will sign the written consent form before being included in the trial. Results will be disseminated through peer-reviewed publications and conference presentations. After the results are published, all de-identified data will be available in the Mendeley database. TRIAL REGISTRATION NUMBER NCT05895643.
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Affiliation(s)
- Mette Kruse Klausen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Tugba Kuzey
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Julie Niemann Pedersen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Signe Keller Justesen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Line Rasmussen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
| | - Ulla B Knorr
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Graeme Mason
- Department of Radiology and Biomedical Imaging, Psychiatry, and Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Claus Thorn Ekstrøm
- Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - George Koob
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | | | - Nora D Volkow
- The National Institute on Drug abuse, National Institutes of Health, Bethesda, MD, USA
| | - Gitte M Knudsen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark
| | - Tina Vilsbøll
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Centre Copenhagen, University of Copenhagen, Herlev, Denmark
| | - Anders Fink-Jensen
- Mental health Centre Copenhagen, Mental Health Services in the Capital Region of Denmark, Frederiksberg, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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10
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Joshi N, Baloch KM, Rukh S, Khan AM, Muskan F, Kumari V, Khan H, Zeeshan M, Azam G, Khalid S, Anwar IB, Ahmed IF, Nishat SM, Gandhi F. Unlocking the potential of glucagon-like peptide-1 receptor agonists in revolutionizing type 2 diabetes management: a comprehensive review. Ann Med Surg (Lond) 2024; 86:7255-7264. [PMID: 39649934 PMCID: PMC11623894 DOI: 10.1097/ms9.0000000000002712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 10/25/2024] [Indexed: 12/11/2024] Open
Abstract
Diabetes mellitus (DM) is a long-term metabolic disorder caused by inadequate production and resistance to insulin. The prevalence of DM is rapidly increasing, with type 2 diabetes (T2D) accounting for more than 90% of cases. Despite new treatments, many patients with T2D do not meet their glycemic targets due to clinical inertia. This review provides an overview of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the management of T2D. The review synthesizes data from clinical trials and meta-analyses on the efficacy, safety, and cost-effectiveness of GLP-1 RAs. It also discusses the mechanisms of action, classification, and barriers to adherence and persistence in therapy. GLP-1 RAs improve glycemic control by lowering A1C levels and promoting weight loss. They have cardioprotective effects and may reduce endothelial inflammation, oxidative stress, and blood pressure. Adherence to GLP-1 RAs is better with once-weekly injections, though gastrointestinal side effects and cost can affect persistence. Semaglutide and liraglutide have shown significant weight reduction, with semaglutide being particularly effective. GLP-1 RAs are cost-effective due to reduced healthcare costs associated with fewer hospitalizations and lower mortality rates. Safety concerns include gastrointestinal issues, pancreatitis, and rare cases of diabetic retinopathy and thyroid C-cell tumors. For clinical practice, GLP-1 RAs represent a valuable option not only for glycemic control but also for weight management and cardiovascular protection. Incorporating GLP-1 RAs into treatment plans can improve patient outcomes, and optimizing dosing regimens and addressing barriers such as cost and side effects are crucial to enhancing patient adherence and long-term treatment success.
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Affiliation(s)
- Nandan Joshi
- Department of Internal Medicine, Surat Municipal Institute of Medical Education and Research, Surat, India
| | - Kanwal Mir Baloch
- Department of Internal Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Shah Rukh
- Department of Internal Medicine, Jinnah Sindh Medical University, Karachi, Pakistan
| | - Abdul Moiz Khan
- Department of Internal Medicine, Sahiwal Medical College, Sahiwal, Pakistan
| | - Fnu Muskan
- Department of Internal Medicine, Khairpur Medical College, Khairpur, Pakistan
| | - Verkha Kumari
- Department of Internal Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Hasher Khan
- Department of Internal Medicine, Dow Medical College, Karachi, Pakistan
| | - Mohd Zeeshan
- Department of Internal Medicine, Career Institute of Medical Sciences and Hospital, Lucknow, India
| | - Ghufran Azam
- Department of Internal Medicine, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan
| | - Saif Khalid
- Department of Internal Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Insa Binte Anwar
- Department of Internal Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Iqra Furqan Ahmed
- Department of Internal Medicine, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Syeed Mahmud Nishat
- Department of Internal Medicine, Shaheed Suhrawardy Medical College, Dhaka, Bangladesh
| | - Fenil Gandhi
- Department of Family Medicine, PGY2, Lower Bucks Hospital, Bristol, PA, USA
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11
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D'Ávila M, Hall S, Horvath TL. GLP-1, GIP, and Glucagon Agonists for Obesity Treatment: A Hunger Perspective. Endocrinology 2024; 165:bqae128. [PMID: 39301751 DOI: 10.1210/endocr/bqae128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/31/2024] [Accepted: 09/19/2024] [Indexed: 09/22/2024]
Abstract
For centuries, increasingly sophisticated methods and approaches have been brought to bear to promote weight loss. Second only to the Holy Grail of research on aging, the idea of finding a single and simple way to lose weight has long preoccupied the minds of laymen and scientists alike. The effects of obesity are far-reaching and not to be minimized; the need for more effective treatments is obvious. Is there a single silver bullet that addresses this issue without effort on the part of the individual? The answer to this question has been one of the most elusive and sought-after in modern history. Now and then, a miraculous discovery propagates the illusion that a simple solution is possible. Now there are designer drugs that seem to accomplish the task: we can lose weight without effort using mono, dual, and triple agonists of receptors for glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. There are, however, fundamental biological principles that raise intriguing questions about these therapies beyond the currently reported side-effects. This perspective reflects upon these issues from the angle of complex goal-oriented behaviors, and systemic and cellular metabolism associated with satiety and hunger.
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Affiliation(s)
- Mateus D'Ávila
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA
| | - Samantha Hall
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA
| | - Tamas L Horvath
- Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06520, USA
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12
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Randolph AB, Zheng H, Rinaman L. Populations of Hindbrain Glucagon-Like Peptide 1 (GLP1) Neurons That Innervate the Hypothalamic PVH, Thalamic PVT, or Limbic Forebrain BST Have Axon Collaterals That Reach All Central Regions Innervated by GLP1 Neurons. J Neurosci 2024; 44:e2063232024. [PMID: 38811166 PMCID: PMC11293452 DOI: 10.1523/jneurosci.2063-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 05/31/2024] Open
Abstract
Neurons in the caudal nucleus of the solitary tract (cNTS) and intermediate reticular nucleus (IRt) that express the glucagon gene (Gcg) give rise to glucagon-like peptide 1 (GLP1)-immunopositive axons in the spinal cord and many subcortical brain regions. Central GLP1 receptor signaling contributes to motivated behavior and stress responses in rats and mice, in which hindbrain GLP1 neurons are activated to express c-Fos in a metabolic state-dependent manner. The present study examined whether GLP1 inputs to distinct brain regions arise from distinct subsets of Gcg-expressing neurons, and mapped the distribution of axon collaterals arising from projection-defined GLP1 neural populations. Using our Gcg-Cre knock-in rat model, Cre-dependent adeno-associated virus (AAV) tracing was conducted in adult male and female rats to compare axonal projections of IRt versus cNTS GLP1 neurons. Overlapping projections were observed in all brain regions that receive GLP1 input, with the caveat that cNTS injections produced Cre-dependent labeling of some IRt neurons, and vice versa. In additional experiments, specific diencephalic or limbic forebrain nuclei were microinjected with Cre-dependent retrograde AAVs (AAVrg) that expressed reporters to fully label the axon collaterals of transduced GLP1 neurons. AAVrg injected into each forebrain site labeled Gcg-expressing neurons in both the cNTS and IRt. The collective axon collaterals of labeled neurons entered the spinal cord and every brain region previously reported to contain GLP1-positive axons. These results indicate that the axons of GLP1 neural populations that innervate the thalamic paraventricular nucleus, paraventricular nucleus of the hypothalamus, and/or bed nucleus of the stria terminalis collectively innervate all central regions that receive GLP1 axonal input.
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Affiliation(s)
- Abigail B Randolph
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32306
| | - Huiyuan Zheng
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32306
| | - Linda Rinaman
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida 32306
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13
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Liu C, Liu WH, Yang W, Chen L, Xue Y, Chen XY. GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice. Neuropharmacology 2024; 252:109946. [PMID: 38599494 DOI: 10.1016/j.neuropharm.2024.109946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/27/2024] [Accepted: 04/07/2024] [Indexed: 04/12/2024]
Abstract
The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.
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Affiliation(s)
- Cui Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China; Department of Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Wen-Hong Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wu Yang
- Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Chen
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Yan Xue
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xin-Yi Chen
- Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.
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14
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Merkel R, Hernandez N, Weir V, Zhang Y, Rich MT, Crist RC, Reiner BC, Schmidt HD. An endogenous GLP-1 circuit engages VTA GABA neurons to regulate mesolimbic dopamine neurons and attenuate cocaine seeking. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.20.599574. [PMID: 38979354 PMCID: PMC11230186 DOI: 10.1101/2024.06.20.599574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate the reinstatement of cocaine-seeking behavior, an animal model of relapse. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA) decreased cocaine reinstatement. Single nuclei transcriptomics and FISH studies revealed GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a novel functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.
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15
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Ruska Y, Csibi A, Dorogházi B, Szilvásy-Szabó A, Mohácsik P, Környei Z, Dénes Á, Kádár A, Puskár Z, Hrabovszky E, Gereben B, Wittmann G, Fekete C. Topography of the GLP-1/GLP-1 receptor system in the spinal cord of male mice. Sci Rep 2024; 14:14403. [PMID: 38909126 PMCID: PMC11193760 DOI: 10.1038/s41598-024-65442-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/20/2024] [Indexed: 06/24/2024] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) agonists are now commonly used to treat type 2 diabetes and obesity. GLP-1R signaling in the spinal cord has been suggested to account for the mild tachycardia caused by GLP-1R agonists, and may also be involved in the therapeutic effects of these drugs. However, the neuroanatomy of the GLP-1/GLP-1R system in the spinal cord is still poorly understood. Here we applied in situ hybridization and immunohistochemistry to characterize this system, and its relation to cholinergic neurons. GLP-1R transcript and protein were expressed in neuronal cell bodies across the gray matter, in matching distribution patterns. GLP-1R-immunolabeling was also robust in dendrites and axons, especially in laminae II-III in the dorsal horn. Cerebrospinal fluid-contacting neurons expressed GLP-1R protein at exceedingly high levels. Only small subpopulations of cholinergic neurons expressed GLP-1R, including a subset of sympathetic preganglionic neurons at the rostral tip of the intermediolateral nucleus. GLP-1 axons innervated all regions where GLP-1R neurons were distributed, except laminae II-III. Scattered preproglucagon (Gcg) mRNA-expressing neurons were identified in the cervical and lumbar enlargements. The results will facilitate further studies on how GLP-1 regulates the sympathetic system and other autonomic and somatic functions via the spinal cord.
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Affiliation(s)
- Yvette Ruska
- Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Szigony Street 43, Budapest, 1083, Hungary
| | - Andrea Csibi
- Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Szigony Street 43, Budapest, 1083, Hungary
| | - Beáta Dorogházi
- Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, 1083, Hungary
| | - Anett Szilvásy-Szabó
- Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Szigony Street 43, Budapest, 1083, Hungary
| | - Petra Mohácsik
- Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, 1083, Hungary
| | - Zsuzsanna Környei
- "Momentum" Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, 1083, Hungary
| | - Ádám Dénes
- "Momentum" Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, 1083, Hungary
| | - Andrea Kádár
- Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Szigony Street 43, Budapest, 1083, Hungary
| | - Zita Puskár
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary
| | - Erik Hrabovszky
- Laboratory of Reproductive Neurobiology, HUN-REN Institute of Experimental Medicine, Budapest, 1083, Hungary
| | - Balázs Gereben
- Laboratory of Molecular Cell Metabolism, HUN-REN Institute of Experimental Medicine, Budapest, 1083, Hungary
| | - Gábor Wittmann
- Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Szigony Street 43, Budapest, 1083, Hungary.
| | - Csaba Fekete
- Laboratory of Integrative Neuroendocrinology, HUN-REN Institute of Experimental Medicine, Szigony Street 43, Budapest, 1083, Hungary.
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16
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Lv P, Li H, Li X, Wang X, Yu J, Gong Y. Intestinal perfusion of unacylated ghrelin alleviated metabolically associated fatty liver disease in rats via a central glucagon-like peptide-1 pathway. Am J Physiol Gastrointest Liver Physiol 2024; 326:G643-G658. [PMID: 38564323 DOI: 10.1152/ajpgi.00217.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/04/2024]
Abstract
Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80%-90% of its circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolically associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanisms. Neuronal retrograde tracking combined with immunofluorescence, central administration of a glucagon-like peptide-1 receptor (GLP-1R) antagonist, and hepatic vagotomy was performed to reveal its possible mechanism involving a central glucagon-like peptide-1 (GLP-1) pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated, and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by the intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonists delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation of MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activation of the GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD.NEW & NOTEWORTHY Intestinal perfusion of UAG, the unacylated form of ghrelin, has shown promising potential for treating MAFLD. This study unveils a potential mechanism involving the central GLP-1 pathway, with UAG upregulating GLP-1R expression and activating GLP-1 neurons in specific brain regions. These findings propose a novel therapeutic strategy for MAFLD treatment through UAG and its modulation of the GLP-1 neuronal pathway.
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Affiliation(s)
- Pengfei Lv
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, People's Republic of China
| | - Hongzeng Li
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, People's Republic of China
| | - Xiangbo Li
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, People's Republic of China
| | - Xueyuying Wang
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, People's Republic of China
| | - Jiantong Yu
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, People's Republic of China
| | - Yanling Gong
- Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, People's Republic of China
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17
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Buller S, Blouet C. Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss. Am J Physiol Endocrinol Metab 2024; 326:E472-E480. [PMID: 38381398 PMCID: PMC11193531 DOI: 10.1152/ajpendo.00250.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 01/05/2024] [Accepted: 02/13/2024] [Indexed: 02/22/2024]
Abstract
New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioral mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood-brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood-brain barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies.
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Affiliation(s)
- Sophie Buller
- Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
| | - Clemence Blouet
- Medical Research Council (MRC) Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom
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18
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Howell JA, Edwards AA, Santollo J. The estrogenic reduction in water intake stimulated by dehydration involves estrogen receptor alpha and a potential role for GLP-1. Physiol Behav 2024; 276:114484. [PMID: 38331374 PMCID: PMC10896180 DOI: 10.1016/j.physbeh.2024.114484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 01/11/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024]
Abstract
It is well documented that estrogens inhibit fluid intake. Most of this research, however, has focused on fluid intake in response to dipsogenic hormone and/or drug treatments in euhydrated rats. Additional research is needed to fully characterize the fluid intake effects of estradiol in response to true hypovolemia. As such, the goals of this series of experiments were to provide a detailed analysis of water intake in response to water deprivation in ovariectomized female rats treated with estradiol. In addition, these experiments also tested if activation of estrogen receptor alpha is sufficient to reduce water intake stimulated by water deprivation and tested for a role of glucagon like peptide-1 in the estrogenic control of water intake. As expected, estradiol reduced water intake in response to 24 and 48 h of water deprivation. The reduction in water intake was associated with a reduction in drinking burst number, with no change in drinking burst size. Pharmacological activation of estrogen receptor alpha reduced intake. Finally, estradiol-treatment caused a leftward shift in the behavioral dose response curve of exendin-4, the glucagon like peptide-1 agonist. While the highest dose of exendin-4 reduced 10 min intake in both oil and estradiol-treated rats, the intermediate dose only reduced intake in rats treated with estradiol. Together, this series of experiments extends previous research by providing a more thorough behavioral analysis of the anti-dipsogenic effect of estradiol in dehydrated rats, in addition to identifying the glucagon like peptide-1 system as a potential bioregulator involved in the underlying mechanisms by which estradiol reduces water intake in the female rat.
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Affiliation(s)
- Julia A Howell
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Andrea A Edwards
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA
| | - Jessica Santollo
- Department of Biology, University of Kentucky, Lexington, KY 40506, USA.
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19
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Wang HJ, Zhang LB, Sun SP, Yan QT, Gao ZQ, Fu FM, Qu MH. Duodenal-jejunal bypass improves hypothalamic oxidative stress and inflammation in diabetic rats via glucagon-like peptide 1-mediated Nrf2/HO-1 signaling. World J Diabetes 2024; 15:287-304. [PMID: 38464379 PMCID: PMC10921169 DOI: 10.4239/wjd.v15.i2.287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/12/2023] [Accepted: 01/12/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is often accompanied by impaired glucose utilization in the brain, leading to oxidative stress, neuronal cell injury and infla-mmation. Previous studies have shown that duodenal jejunal bypass (DJB) surgery significantly improves brain glucose metabolism in T2DM rats, the role and the metabolism of DJB in improving brain oxidative stress and inflammation condition in T2DM rats remain unclear. AIM To investigate the role and metabolism of DJB in improving hypothalamic oxidative stress and inflammation condition in T2DM rats. METHODS A T2DM rat model was induced via a high-glucose and high-fat diet, combined with a low-dose streptozotocin injection. T2DM rats were divided into DJB operation and Sham operation groups. DJB surgical intervention was carried out on T2DM rats. The differential expression of hypothalamic proteins was analyzed using quantitative proteomics analysis. Proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of T2DM rats were analyzed by flow cytometry, quantitative real-time PCR, Western blotting, and immunofluorescence. RESULTS Quantitative proteomics analysis showed significant differences in proteins related to oxidative stress, inflammation, and neuronal injury in the hypothalamus of rats with T2DM-DJB after DJB surgery, compared to the T2DM-Sham groups of rats. Oxidative stress-related proteins (glucagon-like peptide 1 receptor, Nrf2, and HO-1) were significantly increased (P < 0.05) in the hypothalamus of rats with T2DM after DJB surgery. DJB surgery significantly reduced (P < 0.05) hypothalamic inflammation in T2DM rats by inhibiting the activation of NF-κB and decreasing the expression of interleukin (IL)-1β and IL-6. DJB surgery significantly reduced (P < 0.05) the expression of factors related to neuronal injury (glial fibrillary acidic protein and Caspase-3) in the hypothalamus of T2DM rats and upregulated (P < 0.05) the expression of neuroprotective factors (C-fos, Ki67, Bcl-2, and BDNF), thereby reducing hypothalamic injury in T2DM rats. CONCLUSION DJB surgery improve oxidative stress and inflammation in the hypothalamus of T2DM rats and reduce neuronal cell injury by activating the glucagon-like peptide 1 receptor-mediated Nrf2/HO-1 signaling pathway.
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Affiliation(s)
- Huai-Jie Wang
- Translational Medical Center, Weifang Second People's Hospital, Weifang 261041, Shandong Province, China
| | - Li-Bin Zhang
- Department of Endocrinology, Weifang Second People's Hospital, Weifang 261041, Shandong Province, China
| | - Si-Peng Sun
- Translational Medical Center, Weifang Second People's Hospital, Weifang 261041, Shandong Province, China
| | - Qing-Tao Yan
- Department of Pediatric Surgery, Weifang People’s Hospital, Weifang 261041, Shandong Province, China
| | - Zhi-Qin Gao
- School of Bioscience and Technology, Weifang Medical University, Weifang 261053, Shandong Province, China
| | - Fang-Ming Fu
- Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
| | - Mei-Hua Qu
- Translational Medical Center, Weifang Second People's Hospital, Weifang 261041, Shandong Province, China
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Ruska Y, Peterfi Z, Szilvásy-Szabó A, Kővári D, Hrabovszky E, Dorogházi B, Gereben B, Tóth B, Matziari M, Wittmann G, Fekete C. GLP-1 Receptor Signaling Has Different Effects on the Perikarya and Axons of the Hypophysiotropic Thyrotropin-Releasing Hormone Synthesizing Neurons in Male Mice. Thyroid 2024; 34:252-260. [PMID: 38062754 DOI: 10.1089/thy.2023.0284] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
Background: Glucagon-like peptide 1 (GLP-1) is involved in the regulation of energy and glucose homeostasis. As GLP-1 has similar effects on the energy homeostasis as the hypophysiotropic thyrotropin-releasing hormone (TRH) neurons that regulate the hypothalamic-pituitary-thyroid (HPT) axis, we raised the possibility that the TRH neurons are involved in the mediation of the effects of GLP-1. Therefore, the relationship and interaction of the GLP-1 system and the TRH neurons of the hypothalamic paraventricular nucleus (PVN) were studied. Methods: To examine the anatomical and functional relationship of TRH neurons and the GLP-1 system in the PVN, immunocytochemistry, in situ hybridization, in vitro patch-clamp electrophysiology, metabolic phenotyping, and explant experiments were performed. Results: Our data demonstrate that the TRH neurons of the PVN are innervated by GLP-1 producing neurons and express the GLP-1 receptor (GLP-1R). However, not only do the GLP-1-innervated TRH neurons express GLP-1R but the receptor is also present in the axons of the hypophysiotropic TRH neurons in the blood-brain barrier free median eminence (ME) suggesting that peripherally derived GLP-1 may also influence the TRH neurons. In vitro, GLP-1 increased the firing rate of TRH neurons and depolarized them. In addition, GLP-1 directly stimulated the GABAergic input of a population of TRH neurons. Furthermore, GLP-1 inhibited the release of TRH from the hypophysiotropic axons in the ME. In vivo, peripheral GLP-1R agonist administration markedly inhibited the food intake and the energy expenditure, but had no effect on the TRH expression in the PVN and resulted in lower circulating free T4 levels. Conclusions: Our results indicate that GLP-1R activation has a direct stimulatory effect on TRH neurons in the PVN, but the activation of GLP-1R may also inhibit TRH neurons by facilitating their inhibitory inputs or by inhibiting the axon terminals of these cells in the ME. The innervation of TRH neurons by GLP-1 neurons suggests that TRH neurons might be influenced by both circulating GLP-1 and by GLP-1 neurons of the nucleus tractus solitarii. The lack of GLP-1R agonist-induced regulation of TRH neurons in vivo suggests that the HPT axis does not mediate the GLP-1R agonist-induced weight loss.
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Affiliation(s)
- Yvette Ruska
- Laboratory of Integrative Neuroendocrinology; Budapest, Hungary
| | - Zoltan Peterfi
- Laboratory of Integrative Neuroendocrinology; Budapest, Hungary
| | | | - Dóra Kővári
- Laboratory of Integrative Neuroendocrinology; Budapest, Hungary
| | | | - Beáta Dorogházi
- Laboratory of Molecular Cell Metabolism; HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Balázs Gereben
- Laboratory of Molecular Cell Metabolism; HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Blanka Tóth
- Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary
- Department of Molecular Biology, Semmelweis University, Budapest, Hungary
| | - Magdalini Matziari
- Department of Chemistry, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Gábor Wittmann
- Laboratory of Integrative Neuroendocrinology; Budapest, Hungary
| | - Csaba Fekete
- Laboratory of Integrative Neuroendocrinology; Budapest, Hungary
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21
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Liu Y, Gong Y, Li M, Li J. Quercetin protects against hyperglycemia-induced retinopathy in Sprague Dawley rats by regulating the gut-retina axis and nuclear factor erythroid-2-related factor 2 pathway. Nutr Res 2024; 122:55-67. [PMID: 38185061 DOI: 10.1016/j.nutres.2023.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 12/05/2023] [Accepted: 12/12/2023] [Indexed: 01/09/2024]
Abstract
Hyperglycemia-related retinopathy is a disease with a high blindness rate. Recent reports indicate that many flavonol compounds have the potential to prevent the occurrence of disease in the retina by regulating the gut-retina axis. Here, we hypothesized that quercetin could alleviate the symptoms of retinopathy. To clarify the mechanism, Sprague Dawley rats were fed a high-fat diet containing quercetin for 12 weeks and injected with streptozotocin in the ninth week. Additionally, neomycin and ampicillin were used to establish a pseudo-sterile rat model. Afterward, changes in the retina were investigated by using electroretinogram and optical coherence tomography. Blood and tissue samples were collected and biochemical components were analyzed. The extent of intestinal injury was determined via hematoxylin-eosin staining. Microbial community structure was analyzed by using 16S ribosomal RNA sequencing. Finally, the expression of genes was analyzed using real-time polymerase chain reaction. The results showed that quercetin reduced the decline in electroretinography amplitude and outer nuclear layer thickness, increased the activities of antioxidant enzymes, decreased the contents of proinflammatory factors and blood glucose, enhanced the concentration of insulin, and inhibited intestinal dysbiosis and improved gut morphology. Importantly, the underexpression of nuclear factor erythroid-2 related factor 2 in the retina was reversed by quercetin. However, trend changes were no longer significant in most of the indicators after antibiotic treatment. In summary, quercetin has therapeutic effects on retinopathy by regulating the gut-retina axis and nuclear factor erythroid-2 related factor 2 pathway, and the presence of gut microbiota helps quercetin exert its effects on the retina.
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Affiliation(s)
- Yaojie Liu
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Yibo Gong
- Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin Eye Hospital, Tianjin Eye Institute, Tianjin 300384, China
| | - Mengting Li
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China
| | - Jianke Li
- College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an 710119, China.
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22
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Sun HZ, Shen FS, Li XX, Liu C, Xue Y, Han XH, Chen XY, Chen L. Exendin-4 increases the firing activity of hippocampal CA1 neurons through TRPC4/5 channels. Neurosci Res 2024; 199:48-56. [PMID: 37595875 DOI: 10.1016/j.neures.2023.08.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/24/2023] [Accepted: 08/15/2023] [Indexed: 08/20/2023]
Abstract
The central neuropeptide GLP-1 is synthesized by preproglucagon (PPG) neurons in the brain. GLP-1 receptors are widely distributed in central nervous system. Hippocampus is a key component of the limbic system which is involved in learning, memory, and cognition. Previous studies have shown that overexpression of GLP-1 receptors in the hippocampus could improve the process of learning and memory. However, up to now, the direct electrophysiological effects and possible molecular mechanisms of GLP-1 in hippocampal CAl neurons remain unexplored. The present study aims to evaluate the effects and mechanisms of GLP-1 on the spontaneous firing activity of hippocampal CAl neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micro-pressure administration of GLP-1 receptor agonist, exendin-4, significantly increased the spontaneous firing rate of hippocampal CA1 neurons in rats. Furthermore, application of the specific GLP-1 receptor antagonist, exendin(9-39), alone significantly decreased the firing rate of CA1 neurons, suggesting that endogenous GLP-1 modulates the firing activity of CA1 neurons. Co-application of exendin(9-39) completely blocked exendin-4-induced excitation of hippocampal CA1 neurons. Finally, the present study demonstrated for the first time that the transient receptor potential canonical 4 (TRPC4)/TRPC5 channels may be involved in exendin-4-induced excitation. The present studies may provide a rationale for further investigation of the modulation of GLP-1 on learning and memory as well as its possible involvement in Alzheimer's disease.
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Affiliation(s)
- Hui-Zhe Sun
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Fang-Shuai Shen
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiao-Xue Li
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Cui Liu
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Yan Xue
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xiao-Hua Han
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Xin-Yi Chen
- Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Lei Chen
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China.
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Funayama T, Nozu T, Ishioh M, Igarashi S, Sumi C, Saito T, Toki Y, Hatayama M, Yamamoto M, Shindo M, Tanabe H, Okumura T. Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats. Brain Res 2023; 1809:148371. [PMID: 37076092 DOI: 10.1016/j.brainres.2023.148371] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9-39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.
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Affiliation(s)
- Takuya Funayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Japan
| | - Masatomo Ishioh
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Sho Igarashi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Chihiro Sumi
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Takeshi Saito
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Yasumichi Toki
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Mayumi Hatayama
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Masayo Yamamoto
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Motohiro Shindo
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Hiroki Tanabe
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan
| | - Toshikatsu Okumura
- Division of Metabolism, Systemic Bioscience, Gastroenterology and Hematology/Oncology, Department of Medicine, Japan.
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24
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Liu Y, Cao LX, Wang WY, Piao YR, Wang JY, Chu CP, Bing YH, Qiu DL. GLP-1 enhances hyperpolarization-activated currents of mouse cerebellar Purkinje cell in vitro. Front Mol Neurosci 2023; 16:1126447. [PMID: 37089690 PMCID: PMC10113493 DOI: 10.3389/fnmol.2023.1126447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 03/16/2023] [Indexed: 04/08/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is mainly secreted by preglucagonergic neurons in the nucleus tractus solitarius, which plays critical roles in regulation of neuronal activity in the central nervous system through its receptor. In the cerebellar cortex, GLP-1 receptor is abundantly expressed in the molecular layer, Purkinje cell (PC) layer and granular layer, indicating that GLP-1 may modulate the cerebellar neuronal activity. In this study, we investigated the mechanism by which GLP1 modulates mouse cerebellar PC activity in vitro. After blockade of glutamatergic and GABAergic synaptic transmission in PCs, GLP1 increased the spike firing rate accompanied by depolarization of membrane potential and significantly depressed the after-hyperpolarizing potential and outward rectifying current of spike firing discharges via GLP1 receptors. In the presence of TTX and Ba2+, GLP1 significantly enhanced the hyperpolarized membrane potential-evoked instant current, steady current, tail current (I-tail) and hyperpolarization-activated (IH) current. Application of a selective IH channel antagonist, ZD7288, blocked IH and abolished the effect of GLP1 on PC membrane currents. The GLP1 induced enhancement of membrane currents was also abolished by a selective GLP1 receptor antagonist, exendin-9-39, as well as by protein kinase A (PKA) inhibitors, KT5720 and H89. In addition, immunofluorescence detected GLP1 receptor in the mouse cerebellar cortex, mostly in PCs. These results indicated that GLP1 receptor activation enhanced IH channel activity via PKA signaling, resulting in increased excitability of mouse cerebellar PCs in vitro. The present findings indicate that GLP1 plays a critical role in modulating cerebellar function by regulating the spike firing activity of mouse cerebellar PCs.
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Affiliation(s)
- Yang Liu
- Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, Jilin, China
| | - Li-Xin Cao
- Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, Jilin, China
| | - Wei-Yao Wang
- Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin, Jilin, China
| | - Yong-Rui Piao
- Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, Jilin, China
- Department of Urology, Affiliated Hospital of Yanbian University, Yanji, Jilin, China
| | - Jun-Ya Wang
- Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, Jilin, China
| | - Chun-Ping Chu
- Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin, Jilin, China
| | - Yan-Hua Bing
- Functional Experiment Center, College of Medicine, Yanbian University, Yanji, Jilin, China
- *Correspondence: Yan-Hua Bing,
| | - De-Lai Qiu
- Department of Physiology and Pathophysiology, College of Medicine, Yanbian University, Yanji, Jilin, China
- Department of Physiology, College of Basic Medicine, Jilin Medical University, Jilin, Jilin, China
- De-Lai Qiu, ;
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25
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Fang J, Miller P, Grigson PS. Sleep is increased by liraglutide, a glucagon-like peptide-1 receptor agonist, in rats. Brain Res Bull 2023; 192:142-155. [PMID: 36410565 DOI: 10.1016/j.brainresbull.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Sleep disturbances are prominent in drug use disorders, including those involving opioids in both humans and animals. Recent studies have shown that administration of liraglutide, a glucagon-like peptide-1 agonist, significantly reduces heroin taking and seeking in rats. In an effort to further understand the action of this substance on physiological functions and to evaluate safety issues for its potential clinical use, the aim of the present study was to determine whether the dose of liraglutide found effective in reducing responding for an opioid also could improve sleep in drug-naïve rats. METHODS Using a within-subjects design, adult male rats chronically implanted with EEG and EMG electrodes received subcutaneous injection of saline or 0.06, 0.10, 0.30 or 0.60 mg/kg liraglutide. The 0.10 and 0.30 mg/kg doses are known to be most effective in reducing responding for heroin in rats at light or dark onset during a 12:12 h light-dark cycle (0.10 mg/kg for taking and seeking, 0.30 mg/kg for seeking). EEG and EMG were recorded across the 24 h period following each injection. RESULTS After both dark and light onset injections, liraglutide dose-dependently decreased wakefulness and increased non-rapid eye movement (NREM) sleep except at the lowest dose. The bout length of wakefulness and NREM sleep were decreased and increased, respectively. Whether administered at light or dark onset, the above alterations occurred primarily during the dark period (i.e., during the active period). The animals' body weight was decreased after liraglutide treatments as expected since it is clinically used for the treatment of obesity. CONCLUSION These data indicate that liraglutide, at doses known to reduce responding for heroin and fentanyl, also increases NREM sleep, suggesting that the increase in sleep may contribute to the protective effects of liraglutide and may promote overall general health.
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Affiliation(s)
- Jidong Fang
- The Pennsylvania State University College of Medicine, Department of Psychiatry, USA.
| | - Patti Miller
- The Pennsylvania State University College of Medicine, Department of Psychiatry, USA.
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Elevated Glucagon-like Peptide-1 Receptor Level in the Paraventricular Hypothalamic Nucleus of Type 2 Diabetes Mellitus Patients. Int J Mol Sci 2022; 23:ijms232415945. [PMID: 36555587 PMCID: PMC9781792 DOI: 10.3390/ijms232415945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have been approved for the treatment of type 2 diabetes mellitus (T2DM); however, the brain actions of these drugs are not properly established. We used post mortem microdissected human hypothalamic samples for RT-qPCR and Western blotting. For in situ hybridization histochemistry and immunolabelling, parallel cryosections were prepared from the hypothalamus. We developed in situ hybridization probes for human GLP-1R and oxytocin. In addition, GLP-1 and oxytocin were visualized by immunohistochemistry. Radioactive in situ hybridization histochemistry revealed abundant GLP-1R labelling in the human paraventricular hypothalamic nucleus (PVN), particularly in its magnocellular subdivision (PVNmc). Quantitative analysis of the mRNA signal demonstrated increased GLP-1R expression in the PVNmc in post mortem hypothalamic samples from T2DM subjects as compared to controls, while there was no difference in the expression level of GLP-1R in the other subdivisions of the PVN, the hypothalamic dorsomedial and infundibular nuclei. Our results in the PVN were confirmed by RT-qPCR. Furthermore, we demonstrated by Western blot technique that the GLP-1R protein level was also elevated in the PVN of T2DM patients. GLP-1 fibre terminals were also observed in the PVNmc closely apposing oxytocin neurons using immunohistochemistry. The data suggest that GLP-1 activates GLP-1Rs in the PVNmc and that GLP-1R is elevated in T2DM patients, which may be related to the dysregulation of feeding behaviour and glucose homeostasis in T2DM.
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27
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Eugenol alleviated nonalcoholic fatty liver disease in rat via a gut-brain-liver axis involving glucagon-like Peptide-1. Arch Biochem Biophys 2022; 725:109269. [PMID: 35508252 DOI: 10.1016/j.abb.2022.109269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/16/2022]
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Liraglutide Regulates Mitochondrial Quality Control System Through PGC-1α in a Mouse Model of Parkinson's Disease. Neurotox Res 2022; 40:286-297. [PMID: 35043376 DOI: 10.1007/s12640-021-00460-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/05/2021] [Accepted: 12/06/2021] [Indexed: 12/09/2022]
Abstract
Parkinson's disease (PD) is a multifactorial disorder, and there is strong evidence that mitochondria play an essential role in the disorder. Factors that regulate the mechanism of the mitochondrial quality control system have been drawing more and more attention. PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α) is a powerful transcription factor involved in regulation of mitochondrial function. Glucagon-like peptide 1 (GLP-1), a brain-gut peptide, can enter the central nervous system through the blood-brain barrier and play neuroprotective role. However, whether the GLP-1R agonist liraglutide regulates mitochondrial quality control system through PGC-1α is still unclear. We administered different doses of liraglutide to intervene MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD model, and then immunofluorescence, Western blot, and stereotactic injection of lentivirus to downregulate PGC-1α were used to explore the mechanisms underlying the protective effect of liraglutide in PD. The results showed that MPTP lead to decreased mitochondrial biogenesis, disrupted mitochondrial dynamics, inhibited mitochondrial autophagy, and promoted cell apoptosis. While liraglutide effectively attenuated the neurotoxicity of MPTP, including reversing the dyskinesia caused by MPTP and preserving the expression of GLP-1R, TH, and PGC-1α in the substantia nigra (SN), further experiments showed that downregulation of PGC-1α expression via stereotactic injection PGC-1α lentivirus into the SN reversed the liraglutide protective effects. By PGC-1α downregulation, we found that PGC-1α can not only regulate mitochondria biogenesis, mitochondria dynamics, and autophagy, but also regulate cell apoptosis. In summary, liraglutide has a neuroprotective effect in the PD model induced by MPTP. This protective effect is accomplished by activating PGC-1α, which regulates the mitochondrial quality control system.
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Glial Modulation of Energy Balance: The Dorsal Vagal Complex Is No Exception. Int J Mol Sci 2022; 23:ijms23020960. [PMID: 35055143 PMCID: PMC8779587 DOI: 10.3390/ijms23020960] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 02/04/2023] Open
Abstract
The avoidance of being overweight or obese is a daily challenge for a growing number of people. The growing proportion of people suffering from a nutritional imbalance in many parts of the world exemplifies this challenge and emphasizes the need for a better understanding of the mechanisms that regulate nutritional balance. Until recently, research on the central regulation of food intake primarily focused on neuronal signaling, with little attention paid to the role of glial cells. Over the last few decades, our understanding of glial cells has changed dramatically. These cells are increasingly regarded as important neuronal partners, contributing not just to cerebral homeostasis, but also to cerebral signaling. Our understanding of the central regulation of energy balance is part of this (r)evolution. Evidence is accumulating that glial cells play a dynamic role in the modulation of energy balance. In the present review, we summarize recent data indicating that the multifaceted glial compartment of the brainstem dorsal vagal complex (DVC) should be considered in research aimed at identifying feeding-related processes operating at this level.
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30
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Chen XY, Chen L, Yang W, Xie AM. GLP-1 Suppresses Feeding Behaviors and Modulates Neuronal Electrophysiological Properties in Multiple Brain Regions. Front Mol Neurosci 2022; 14:793004. [PMID: 34975402 PMCID: PMC8718614 DOI: 10.3389/fnmol.2021.793004] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/29/2021] [Indexed: 11/24/2022] Open
Abstract
The glucagon-like peptide-1 (GLP-1) plays important roles in the regulation of food intake and energy metabolism. Peripheral or central GLP-1 suppresses food intake and reduces body weight. The electrophysiological properties of neurons in the mammalian central nervous system reflect the neuronal excitability and the functional organization of the brain. Recent studies focus on elucidating GLP-1-induced suppression of feeding behaviors and modulation of neuronal electrophysiological properties in several brain regions. Here, we summarize that activation of GLP-1 receptor (GLP-1R) suppresses food intake and induces postsynaptic depolarization of membrane potential and/or presynaptic modulation of glutamatergic or GABAergic neurotransmission in brain nuclei located within the medulla oblongata, pons, mesencephalon, diencephalon, and telencephalon. This review may provide a background to guide future research about the cellular mechanisms of GLP-1-induced feeding inhibition.
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Affiliation(s)
- Xin-Yi Chen
- Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.,Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lei Chen
- Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wu Yang
- Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China
| | - An-Mu Xie
- Department of Neurology, Affiliated Hospital of Qingdao University, Qingdao, China
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31
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Colvin KJ, Killen HS, Kanter MJ, Halperin MC, Engel L, Dickinson MB, Fimmel AI, Holland JG, Currie PJ. Differential effects of intra-ventral tegmental area ghrelin and glucagon-like peptide-1 on the stimulatory action of D-amphetamine and cocaine-induced ethanol intake in male Sprague Dawley rats. Behav Brain Res 2021; 421:113726. [PMID: 34954300 DOI: 10.1016/j.bbr.2021.113726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 12/24/2022]
Abstract
In order to further elucidate the role of mesolimbic peptides in the expression of ethanol reward, the present study investigated the effects of ghrelin and glucagon-like peptide-1 (GLP-1) on ethanol intake, in addition to ethanol intake stimulated by systemic d-amphetamine or cocaine treatment. While a number of studies suggest that ghrelin plays an important role in mesolimbic reward, emerging data now indicate that GLP-1 receptor mechanisms inhibit reward signaling, possibly by directly or indirectly inhibiting ghrelinergic activity within the mesolimbic system. In the present study all rats were initially habituated to a 6% ethanol solution. We then demonstrated that intraperitoneal injections of d-amphetamine and cocaine increased ethanol intake compared to the vehicle condition. In subsequent testing we examined the effects of ventral tegmental area (VTA) ghrelin or vehicle paired with a fixed dose of d-amphetamine or vehicle. In separate rats we then investigated the impact of the GLP-1 agonist exendin-4 (Ex-4), injected into the VTA, on ethanol intake alone, or when Ex-4 was co-administered with d-amphetamine or cocaine. Our results indicated that VTA ghrelin significantly increased ethanol intake, and most importantly, potentiated the effect of d-amphetamine and cocaine on ethanol consumption. Conversely, VTA Ex-4 inhibited ethanol intake and antagonized the stimulatory effect of d-amphetamine and cocaine on ethanol consumption. In a final study we further demonstrated that VTA Ex-4 treatment significantly inhibited the combined stimulatory effects of ghrelin paired with d-amphetamine or ghrelin paired with cocaine. Overall our findings are consistent with a critical role for both ghrelin and GLP-1 receptor mechanisms in mesolimbic ethanol reward circuitry. Moreover, our results further suggest that ghrelin and GLP-1 modulate the stimulatory effect of psychostimulants on ethanol intake.
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Affiliation(s)
- Kayla J Colvin
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Henry S Killen
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Maxwell J Kanter
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Maximilian C Halperin
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Liv Engel
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Matthew B Dickinson
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Anna I Fimmel
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - James G Holland
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA
| | - Paul J Currie
- Department of Psychology, Reed College, 3203 SE Woodstock Blvd., Portland, OR 97202, USA.
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Ast J, Broichhagen J, Hodson DJ. Reagents and models for detecting endogenous GLP1R and GIPR. EBioMedicine 2021; 74:103739. [PMID: 34911028 PMCID: PMC8669301 DOI: 10.1016/j.ebiom.2021.103739] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/12/2021] [Accepted: 11/23/2021] [Indexed: 01/18/2023] Open
Abstract
Glucagon-like peptide-1 receptor (GLP1R) agonists target the GLP1R, whereas dual GLP1R/ gastric inhibitory polypeptide receptor (GIPR) agonists target both the GLP1R and GIPR. Despite the importance of these drug classes for the treatment of diabetes and obesity, still very little is known about the localization of GLP1R and GIPR themselves. Complicating matters is the low abundance of GLP1R and GIPR mRNA/protein, as well as a lack of specific and validated reagents for their detection. Without knowing where GLP1R and GIPR are located, it is difficult to propose mechanisms of action in the various target organs, and whether this is indirect or direct. In the current review, we will explain the steps needed to properly validate reagents for endogenous GLP1R/GIPR detection, describe the available approaches to visualize GLP1R/GIPR, and provide an update on the state-of-art. The overall aim is to provide a reference resource for researchers interested in GLP1R and GIPR signaling.
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Affiliation(s)
- Julia Ast
- Institute of Metabolism and Systems Research (IMSR), Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
| | | | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR), Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.
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Expression of glucagon-like peptide 1 receptor in neuropeptide Y neurons of the arcuate nucleus in mice. Brain Struct Funct 2021; 227:77-87. [PMID: 34596755 DOI: 10.1007/s00429-021-02380-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 09/02/2021] [Indexed: 10/20/2022]
Abstract
Glucagon-like peptide 1 (GLP-1) and its agonists exert anorexigenic effect at least partly via acting on GLP-1 receptors (GLP-1R) in the arcuate nucleus (ARC). While the anorexigenic, proopiomelanocortin (POMC) neurons of the ARC were shown previously to express GLP-1R, the putative GLP-1R-content of the orexigenic, neuropeptide Y (NPY) neurons remained so far undetected. As GLP-1R is abundant in the ventromedial ARC, where NPY neurons are located; here, we address the possibility that GLP-1 can act directly on the orexigenic NPY system via GLP-1R. Double-labeling immunocytochemistry and in situ hybridization were performed on tissues of adult male mice to detect GLP-1R in NPY neurons. In double-immunolabeled preparations, GLP-1R-immunoreactivity was observed in NPY neurons and in axons ensheathing the majority of NPY neurons. Ultrastructural studies confirmed that GLP-1R-immunoreactivity is associated with the outer membrane of NPY perikarya as well as with axons forming symmetric type, inhibitory synapses on NPY-containing neurons. Double-labeling in situ hybridization experiments demonstrated the expression of GLP-1R mRNA in approximately 20% of NPY mRNA-containing neurons of the ARC. In summary, our data demonstrate the presence of GLP-1R protein and mRNA in NPY neurons of ARC and also reveal the innervation of NPY neurons by GLP-1R-containing inhibitory neurons. These observations suggest that GLP-1 signaling can influence NPY neurons both directly and indirectly. Furthermore, GLP-1 signaling on energy homeostasis appears to involve both direct and indirect effects of GLP-1 on the orexigenic NPY neurons, in addition to the previously known effects via the anorexigenic POMC neuronal system.
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Jing F, Zou Q, Wang Y, Cai Z, Tang Y. Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation. J Headache Pain 2021; 22:86. [PMID: 34325647 PMCID: PMC8323319 DOI: 10.1186/s10194-021-01302-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 07/21/2021] [Indexed: 12/30/2022] Open
Abstract
Background Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway. Supplementary Information The online version contains supplementary material available at 10.1186/s10194-021-01302-x.
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Affiliation(s)
- Feng Jing
- Department of Histology and Embryology, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China.,Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, No.118 Xingguang Avenue, Liangjiang New Area, 401147, Chongqing, China
| | - Qian Zou
- Chongqing Key Laboratory of Neurodegenerative Diseases, No.312 Zhongshan First Road, Yuzhong District, 400013, Chongqing, China
| | - Yangyang Wang
- Chongqing Key Laboratory of Neurodegenerative Diseases, No.312 Zhongshan First Road, Yuzhong District, 400013, Chongqing, China
| | - Zhiyou Cai
- Department of Neurology, Chongqing General Hospital, University of Chinese Academy of Sciences, No.118 Xingguang Avenue, Liangjiang New Area, 401147, Chongqing, China. .,Chongqing Key Laboratory of Neurodegenerative Diseases, No.312 Zhongshan First Road, Yuzhong District, 400013, Chongqing, China.
| | - Yong Tang
- Department of Histology and Embryology, Chongqing Medical University, No.1 Yixueyuan Road, Yuzhong District, 400016, Chongqing, China.
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Povysheva N, Zheng H, Rinaman L. Glucagon-like peptide 1 receptor-mediated stimulation of a GABAergic projection from the bed nucleus of the stria terminalis to the hypothalamic paraventricular nucleus. Neurobiol Stress 2021; 15:100363. [PMID: 34277897 PMCID: PMC8271176 DOI: 10.1016/j.ynstr.2021.100363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/25/2021] [Accepted: 06/26/2021] [Indexed: 01/14/2023] Open
Abstract
We previously reported that GABAergic neurons within the ventral anterior lateral bed nucleus of the stria terminalis (alBST) express glucagon-like peptide 1 receptor (GLP1R) in rats, and that virally-mediated “knock-down” of GLP1R expression in the alBST prolongs the hypothalamic-pituitary-adrenal axis response to acute stress. Given other evidence that a GABAergic projection pathway from ventral alBST serves to limit stress-induced activation of the HPA axis, we hypothesized that GLP1 signaling promotes activation of GABAergic ventral alBST neurons that project directly to the paraventricular nucleus of the hypothalamus (PVN). After PVN microinjection of fluorescent retrograde tracer followed by preparation of ex vivo rat brain slices, whole-cell patch clamp recordings were made in identified PVN-projecting neurons within the ventral alBST. Bath application of Exendin-4 (a specific GLP1R agonist) indirectly depolarized PVN-projecting neurons in the ventral alBST and adjacent hypothalamic parastrial nucleus (PS) through a network-dependent increase in excitatory synaptic inputs, coupled with a network-independent reduction in inhibitory inputs. Additional retrograde tracing experiments combined with in situ hybridization confirmed that PVN-projecting neurons within the ventral alBST/PS are GABAergic, and do not express GLP1R mRNA. Conversely, GLP1R mRNA is expressed by a subset of neurons that project into the ventral alBST and were likely contained within coronal ex vivo slices, including GABAergic neurons within the oval subnucleus of the dorsal alBST and glutamatergic neurons within the substantia innominata. Our novel findings reveal potential GLP1R-mediated mechanisms through which the alBST exerts inhibitory control over the endocrine HPA axis.
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Affiliation(s)
- Nadya Povysheva
- Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Huiyuan Zheng
- Department of Psychology, Program in Neuroscience, Florida State University, Tallahassee, FL, 32306, USA
| | - Linda Rinaman
- Department of Psychology, Program in Neuroscience, Florida State University, Tallahassee, FL, 32306, USA
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Holt MK, Rinaman L. The role of nucleus of the solitary tract glucagon-like peptide-1 and prolactin-releasing peptide neurons in stress: anatomy, physiology and cellular interactions. Br J Pharmacol 2021; 179:642-658. [PMID: 34050926 PMCID: PMC8820208 DOI: 10.1111/bph.15576] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/04/2021] [Accepted: 05/17/2021] [Indexed: 02/06/2023] Open
Abstract
Neuroendocrine, behavioural and autonomic responses to stressful stimuli are orchestrated by complex neural circuits. The caudal nucleus of the solitary tract (cNTS) in the dorsomedial hindbrain is uniquely positioned to integrate signals of both interoceptive and psychogenic stress. Within the cNTS, glucagon‐like peptide‐1 (GLP‐1) and prolactin‐releasing peptide (PrRP) neurons play crucial roles in organising neural responses to a broad range of stressors. In this review we discuss the anatomical and functional overlap between PrRP and GLP‐1 neurons. We outline their co‐activation in response to stressful stimuli and their importance as mediators of behavioural and physiological stress responses. Finally, we review evidence that PrRP neurons are downstream of GLP‐1 neurons and outline unexplored areas of the research field. Based on the current state‐of‐knowledge, PrRP and GLP‐1 neurons may be compelling targets in the treatment of stress‐related disorders.
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Affiliation(s)
- Marie K Holt
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Linda Rinaman
- Department of Psychology and Program in Neuroscience, Florida State University, Tallahassee, Florida, USA
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