{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:42:09Z","timestamp":1791420129441,"version":"4.3.3"},"reference-count":81,"publisher":"Bioscientifica","issue":"4","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,21]]},"abstract":"<jats:p>G protein-coupled receptors (GPCRs) have a critical role in energy homeostasis, contributing to food intake, energy expenditure and glycaemic control. Dysregulation of energy expenditure can lead to metabolic syndrome (abdominal obesity, elevated plasma triglyceride, LDL cholesterol and glucose, and high blood pressure), which is associated with an increased risk of developing obesity, diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular complications. As the prevalence of these chronic diseases continues to rise worldwide, there is an increased need to understand the molecular mechanisms by which energy expenditure is regulated to facilitate the development of effective therapeutic strategies to treat and prevent these conditions. In recent years, drugs targeting GPCRs have been the focus of efforts to improve treatments for type-2 diabetes and obesity, with GLP-1R agonists a particular success. In this review, we focus on nine GPCRs with roles in energy homeostasis that are current and emerging targets to treat obesity and diabetes. We discuss findings from pre-clinical models and clinical trials of drugs targeting these receptors and challenges that must be overcome before these drugs can be routinely used in clinics. We also describe new insights into how these receptors signal, including how accessory proteins, biased signalling, and complex spatial signalling could provide unique opportunities to develop more efficacious therapies with fewer side effects. Finally, we describe how combined therapies, in which multiple GPCRs are targeted, may improve clinical outcomes and reduce off-target effects.<\/jats:p>","DOI":"10.1530\/jme-23-0014","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T10:06:46Z","timestamp":1679393206000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":14,"title":["RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis"],"prefix":"10.1530","volume":"70","author":[{"given":"Aqfan","family":"Jamaluddin","sequence":"first","affiliation":[{"name":"Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham, UK"},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1361-9174","authenticated-orcid":true,"given":"Caroline M","family":"Gorvin","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research (IMSR) and Centre for Diabetes, Endocrinology and Metabolism (CEDAM), University of Birmingham, Birmingham, UK"},{"name":"Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"bib1","series-title":"Cell Metabolism","article-title":"Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake","volume":"30","author":"Adriaenssens","year":"2019","unstructured":"Adriaenssens AEBiggs EKDarwish TTadross JSukthankar TGirish MPolex-Wolf JLam BYZvetkova IPan W, 2019Glucose-dependent insulinotropic polypeptide receptor-expressing cells in the hypothalamus regulate food intake. 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