{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:20:03Z","timestamp":1791382803012,"version":"4.3.3"},"reference-count":52,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce bodyweight and blood glucose. Extensive evidence from randomized controlled trials has indicated that GLP-1RAs have benefits well beyond weight loss and glucose control, extending from reductions in cardiovascular mortality to reductions in prostate cancer risk. Notably, some benefits of GLP-1RAs for the cardiovascular\u2013kidney\u2013metabolic (CKM) system arise before weight loss occurs for reasons that are not entirely clear but are key to patient care and drug development. Here, we hypothesize that GLP-1RAs act by inducing calorie restriction and by activating adenosine monophosphate-activated protein kinase (AMPK), which not only provides an explanation for the unique effectiveness of GLP-1RAs but also indicates a common mechanism shared by effective CKM therapies, including salicylates, metformin, statins, healthy diet, and physical activity. Whether AMPK activation is obligatory for effective CKM therapies should be considered. As such, we propose a mechanism of action for GLP-1RAs and explain how it provides an overarching framework for identifying means of preventing and treating cardiovascular, kidney, metabolic and related diseases, as well as informing the complementary question as to the components of a healthy lifestyle.<\/jats:p>","DOI":"10.3390\/life15020253","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T04:00:28Z","timestamp":1738900828000},"page":"253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Hypothesis That Glucagon-like Peptide-1 Receptor Agonists Exert Immediate and Multifaceted Effects by Activating Adenosine Monophosphate-Activate Protein Kinase (AMPK)"],"prefix":"10.3390","volume":"15","author":[{"given":"C. Mary","family":"Schooling","sequence":"first","affiliation":[{"name":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"},{"name":"School of Public Health and Health Policy, City University of New York, Graduate School of Public Health and Health Policy, 55 W 125th St, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4387-386X","authenticated-orcid":false,"given":"Guoyi","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-6062","authenticated-orcid":false,"given":"Ghada A.","family":"Soliman","sequence":"additional","affiliation":[{"name":"School of Public Health and Health Policy, City University of New York, Graduate School of Public Health and Health Policy, 55 W 125th St, New York, NY 10027, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel M.","family":"Leung","sequence":"additional","affiliation":[{"name":"School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106094","DOI":"10.1016\/j.phrs.2022.106094","article-title":"Antidiabetic medications and the risk of prostate cancer in patients with diabetes mellitus: A systematic review and meta-analysis","volume":"177","author":"Cui","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e074068","DOI":"10.1136\/bmj-2022-074068","article-title":"Benefits and harms of drug treatment for type 2 diabetes: Systematic review and network meta-analysis of randomised controlled trials","volume":"381","author":"Shi","year":"2023","journal-title":"BMJ"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/d41586-024-01564-w","article-title":"Ozempic keeps wowing: Trial data show benefits for kidney disease","volume":"630","author":"Fairbank","year":"2024","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1161\/CIR.0000000000001186","article-title":"A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2778","DOI":"10.1210\/clinem\/dgaa259","article-title":"Effect of Glucagon on Ischemic Heart Disease and Its Risk Factors: A Mendelian Randomization Study","volume":"105","author":"Ng","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"142","DOI":"10.4103\/2230-8210.172242","article-title":"Newer antidiabetic drugs and calorie restriction mimicry","volume":"20","author":"Kalra","year":"2016","journal-title":"Indian J. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1111\/dom.12932","article-title":"Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity","volume":"19","author":"Blundell","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1126\/science.abm7649","article-title":"Metabolic scaling is the product of life-history optimization","volume":"377","author":"White","year":"2022","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eadh4990","DOI":"10.1126\/sciadv.adh4990","article-title":"Evidence for the role of selection for reproductively advantageous alleles in human aging","volume":"9","author":"Long","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S2213-8587(19)30151-2","article-title":"2 years of calorie restriction and cardiometabolic risk (CALERIE): Exploratory outcomes of a multicentre, phase 2, randomised controlled trial","volume":"7","author":"Kraus","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S0140-6736(51)91210-X","article-title":"Mortality from circulatory diseases in Norway 1940\u20131945","volume":"1","author":"Strom","year":"1951","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1001\/jama.1920.02620060015005","article-title":"The effect of food restriction during war on mortality in Copenhagen","volume":"74","author":"Hindhede","year":"1920","journal-title":"J. Am. Med. Assoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.cmet.2016.12.009","article-title":"Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex","volume":"25","author":"Howell","year":"2017","journal-title":"Cell Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101922","DOI":"10.1016\/j.clinre.2022.101922","article-title":"The mTORC1\/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice","volume":"46","author":"Marinho","year":"2022","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/s41580-022-00547-x","article-title":"New insights into activation and function of the AMPK","volume":"24","author":"Steinberg","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1007\/s00125-023-05973-w","article-title":"Incretins and cardiovascular disease: To the heart of type 2 diabetes?","volume":"66","author":"Solini","year":"2023","journal-title":"Diabetologia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1097\/MNH.0000000000000349","article-title":"Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease","volume":"26","author":"Rajani","year":"2017","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/S2213-8587(21)00203-5","article-title":"Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of randomised trials","volume":"9","author":"Sattar","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12450","DOI":"10.1096\/fj.202000164R","article-title":"The novel non-steroidal MR antagonist finerenone improves metabolic parameters in high-fat diet-fed mice and activates brown adipose tissue via AMPK-ATGL pathway","volume":"34","author":"Marzolla","year":"2020","journal-title":"Faseb J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"118321","DOI":"10.1016\/j.jep.2024.118321","article-title":"Cordyceps: Alleviating Ischemic Cardiovascular and Cerebrovascular Injury\u2014A Comprehensive Review","volume":"332","author":"Li","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41586-022-05006-3","article-title":"Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion","volume":"608","author":"Wang","year":"2022","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2403347","article-title":"Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes","volume":"391","author":"Perkovic","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Schooling, C.M., Au Yeung, S.L., Freeman, G., and Cowling, B.J. (2013). The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med., 11.","DOI":"10.1186\/1741-7015-11-57"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.2337\/dc20-1558","article-title":"Rapid Changes in Serum Testosterone in Men With Newly Diagnosed Type 2 Diabetes With Intensive Insulin and Metformin","volume":"44","author":"Hu","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e58567","DOI":"10.7554\/eLife.58567","article-title":"Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation","volume":"9","author":"Schooling","year":"2020","journal-title":"eLife"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.fertnstert.2022.04.027","article-title":"Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: A randomized placebo-controlled-phase 3 study","volume":"118","author":"Chappell","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lengsfeld, S., Probst, L., Emara, Y., Werlen, L., Vogt, D.R., Bathelt, C., Baur, F., Caviezel, B., Vukajlovic, T., and Fischer, M. (2024). Effects of the glucagon-like peptide-1 receptor agonist dulaglutide on sexuality in healthy men: A randomised, double-blind, placebo-controlled crossover study. eBioMedicine, 107.","DOI":"10.1016\/j.ebiom.2024.105284"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhao, J.V., and Schooling, C.M. (2020). The role of testosterone in chronic kidney disease and kidney function in men and women: A bi-directional Mendelian randomization study in the UK Biobank. BMC Med., 18.","DOI":"10.1186\/s12916-020-01594-x"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"875","DOI":"10.18632\/aging.100098","article-title":"Macronutrient balance and lifespan","volume":"1","author":"Simpson","year":"2009","journal-title":"Aging"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41586-024-08026-3","article-title":"Dietary restriction impacts health and lifespan of genetically diverse mice","volume":"634","author":"Deighan","year":"2024","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Vara-Ciruelos, D., Russell, F.M., and Hardie, D.G. (2019). The strange case of AMPK and cancer: Dr Jekyll or Mr Hyde?. Open Biol., 9.","DOI":"10.1098\/rsob.190099"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tang, H., Zhang, B., Lu, Y., Donahoo, W.T., Singh Ospina, N., Kotecha, P., Lu, Y., Tong, J., Smith, S.M., and Rosenberg, E.I. (2024). Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials. Diabetes Obes. Metab., Online ahead of print.","DOI":"10.1111\/dom.16147"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1007\/s00125-023-05925-4","article-title":"Genetically proxied glucose-lowering drug target perturbation and risk of cancer: A Mendelian randomisation analysis","volume":"66","author":"Yarmolinsky","year":"2023","journal-title":"Diabetologia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1016\/j.jacc.2024.08.007","article-title":"The Effect of Semaglutide on Mortality and COVID-19-Related Deaths: An Analysis From the SELECT Trial","volume":"84","author":"Scirica","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1053\/j.gastro.2007.03.054","article-title":"Biology of incretins: GLP-1 and GIP","volume":"132","author":"Baggio","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.2337\/db14-0302","article-title":"GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK","volume":"63","author":"Beiroa","year":"2014","journal-title":"Diabetes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"R1427","DOI":"10.1152\/ajpregu.00479.2002","article-title":"Peptides that regulate food intake: Glucagon-like peptide 1-(7-36) amide acts at lateral and medial hypothalamic sites to suppress feeding in rats","volume":"284","author":"Schick","year":"2003","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E651","DOI":"10.1152\/ajpendo.00113.2017","article-title":"The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity","volume":"313","author":"Burmeister","year":"2017","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41586-024-07685-6","article-title":"Dissociable hindbrain GLP1R circuits for satiety and aversion","volume":"632","author":"Huang","year":"2024","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.brainresbull.2018.11.016","article-title":"Hindbrain dorsal vagal complex AMPK controls hypothalamic gluco-regulatory transmitter and counter-regulatory hormone responses to hypoglycemia","volume":"144","author":"Mandal","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"34","DOI":"10.2337\/db15-0973","article-title":"Knockdown of GLP-1 Receptors in Vagal Afferents Affects Normal Food Intake and Glycemia","volume":"65","author":"Krieger","year":"2016","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3945\/an.112.002071","article-title":"Brain responses to high-protein diets","volume":"3","author":"Journel","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"110988","DOI":"10.1016\/j.ygeno.2025.110988","article-title":"Mechanistic insights into GLP-1 receptor agonist-induced weight loss through ceRNA network analysis","volume":"117","author":"Li","year":"2025","journal-title":"Genomics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1161\/ATVBAHA.124.321850","article-title":"Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease","volume":"45","author":"Stone","year":"2024","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1007\/s12035-012-8239-z","article-title":"Glucagon-like peptide 1 (GLP-1) can reverse AMP-activated protein kinase (AMPK) and S6 kinase (P70S6K) activities induced by fluctuations in glucose levels in hypothalamic areas involved in feeding behaviour","volume":"45","author":"Sanz","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1530\/JME-18-0212","article-title":"Effects of CCK-8 and GLP-1 on fatty acid sensing and food intake regulation in trout","volume":"62","author":"Velasco","year":"2019","journal-title":"J. Mol. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/nature11862","article-title":"Metabolism of inflammation limited by AMPK and pseudo-starvation","volume":"493","author":"Hardie","year":"2013","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12933-022-01585-7","article-title":"Impact of semaglutide on high-sensitivity C-reactive protein: Exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials","volume":"21","author":"Mosenzon","year":"2022","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.2147\/JIR.S276982","article-title":"Insights into the Role of Inflammation in the Management of Atherosclerosis","volume":"16","author":"Rocha","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1748-1716.2009.01972.x","article-title":"LKB1 and AMP-activated protein kinase control of mTOR signalling and growth","volume":"196","author":"Shaw","year":"2009","journal-title":"Acta Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Gill, D., Dib, M.J., Cronj\u00e9, H.T., Karhunen, V., Woolf, B., Gagnon, E., Daghlas, I., Nyberg, M., Drakeman, D., and Burgess, S. (2024). Common pitfalls in drug target Mendelian randomization and how to avoid them. BMC Med., 22.","DOI":"10.1186\/s12916-024-03700-9"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/2\/253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:28:32Z","timestamp":1760027312000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/2\/253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,7]]},"references-count":52,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["life15020253"],"URL":"https:\/\/doi.org\/10.3390\/life15020253","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,7]]}}}