{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T17:04:14Z","timestamp":1783443854191,"version":"3.54.6"},"reference-count":69,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF22SA0079901"],"award-info":[{"award-number":["NNF22SA0079901"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF23SA0084103"],"award-info":[{"award-number":["NNF23SA0084103"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF22OC0073778"],"award-info":[{"award-number":["NNF22OC0073778"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF24OC0089508"],"award-info":[{"award-number":["NNF24OC0089508"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"\n Abstract<\/jats:title>\n \n Glucagon receptor agonism, particularly when combined with incretin analogues, is currently being explored as a treatment for obesity to improve cardiometabolic health, given glucagon's key role in regulating energy homoeostasis. However, male\u2010biased preclinical studies limit our understanding of sex\u2010specific responses to glucagon receptor activation, especially regarding fibroblast growth factor 21 (FGF21), a major downstream effector of glucagon signalling. To test whether responses to glucagon receptor agonism are sex dependent and modulated by FGF21, we compared a long\u2010acting glucagon analogue (LA\u2010Gcg) with the GLP\u20101 analogue semaglutide in diet\u2010induced obese male and female mice. We then used female Fgf21 knockout (KO) mice to probe the role of the FGF21\u2010glucagon axis in the response to glucagon receptor agonism. LA\u2010Gcg induced greater weight loss, reduced food intake and more strongly altered hepatic gene expression in males, whereas semaglutide effects were comparable between sexes. LA\u2010Gcg impaired glucose tolerance more severely in females than in males. This impairment was exacerbated in female Fgf21 KO mice, despite similar reductions in body weight between genotypes. Notably, FGF21 deficiency potentiated diet\u2010induced obesity in females but had minimal impact under chow diet, fasting or voluntary exercise. Collectively,\u00a0these findings reveal that both sex and FGF21 modulate metabolic responses to glucagon\u2010based therapies, emphasizing the importance of including female models in preclinical metabolic research to better predict therapeutic efficacy.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Biological sex is known to affect metabolism, yet this variable remains largely underexplored in metabolic research. In males, glucagon's metabolic benefits often involve another hormone, FGF21 (fibroblast growth factor 21), but this relationship is largely unstudied in females.<\/jats:p>\n <\/jats:list-item>\n \n A long\u2010acting glucagon (LA\u2010Gcg) treatment caused less weight loss in obese female mice, failing to reduce their food intake, unlike in males. LA\u2010Gcg also worsened glucose tolerance in females.<\/jats:p>\n <\/jats:list-item>\n \n \n Female mice lacking the\n Fgf21<\/jats:italic>\n gene were more susceptible to diet\u2010induced obesity; although LA\u2010Gcg treatment still reduced their weight and cleared liver fat, the absence of FGF21 worsened the drug\u2010induced glucose intolerance.\n <\/jats:p>\n <\/jats:list-item>\n \n Our findings highlight sex\u2010specific differences in metabolic responses to glucagon, emphasizing the need to consider sex as a key variable in the development of glucagon\u2010based therapies.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp289817","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T14:39:14Z","timestamp":1775227154000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sex\u2010specific metabolic responses to glucagon receptor agonism and modulation of the FGF21\u2010glucagon axis in female mice"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5076-1534","authenticated-orcid":false,"given":"Christoffer","family":"Merrild","sequence":"first","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8288-1459","authenticated-orcid":false,"given":"Valdemar Brimnes Ingemann","family":"Johansen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2456-9667","authenticated-orcid":false,"given":"Christoffer","family":"Clemmensen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6478-3815","authenticated-orcid":false,"given":"Pablo","family":"Ranea\u2010Robles","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark"},{"name":"Department of Physiology, Faculty of Medicine University of Granada Granada Spain"},{"name":"Biotechnology Institute, Biomedical Research Center (CIBM) University of Granada Granada Spain"},{"name":"Sport and Health University Research Institute (iMUDS), University of Granada Granada Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria Ibs.Granada Granada Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.molmet.2019.02.002","article-title":"Activation of hepatic estrogen receptor\u2010\u03b1 increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice","volume":"22","author":"Allard C.","year":"2019","journal-title":"Molecular Metabolism"},{"issue":"3","key":"e_1_2_6_3_1","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/s00125-012-2803-y","article-title":"Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: A novel mechanism of glucagon\u2010stimulated lipolysis?","volume":"56","author":"Arafat A. 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