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Thus, glucagon provides a switch from hepatic glucose and lipid storage towards lipid and amino acid breakdown fueling glucose production during fasting. However, the effects of genetic deletion of the glucagon receptor on lipid metabolism are unclear. We therefore assessed parameters of lipid metabolism in fasted and non\u2010fasted male and female mice with permanent whole\u2010body deletion of the glucagon receptor (<jats:italic>Gcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice). To investigate whether <jats:italic>Gcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice tolerated a diet promoting metabolic dysfunction\u2010associated steatohepatitis (MASH) and steatosis, we fed female <jats:italic>Gcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice the Gubra Amylin Nonalcoholic steatohepatitis (GAN) diet and high\u2010fat diet (HFD), respectively. We found that non\u2010fasted <jats:italic>Gcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice fed standard chow showed hypercholesterolemia and increased liver fat (borderline significant in non\u2010fasted male <jats:italic>Gcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, but significant in the remaining groups). In the fasted state these changes were insignificant due to fasting\u2010induced steatosis. When challenged with a GAN diet and HFD, female <jats:italic>Gcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice were prone to steatosis and dyslipidemia but resistant to weight gain. Taken together, our data highlight glucagon as an important physiological regulator of not just glucose, but also hepatic lipid metabolism.<\/jats:p>","DOI":"10.14814\/phy2.70235","type":"journal-article","created":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T05:17:31Z","timestamp":1740201451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Female glucagon receptor knockout mice are prone to steatosis but resistant to weight gain when fed a <scp>MASH<\/scp>\u2010promoting <scp>GAN<\/scp> diet and a high\u2010fat diet"],"prefix":"10.14814","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5679-2807","authenticated-orcid":false,"given":"Katrine D.","family":"Galsgaard","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"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"}]},{"given":"Emilie","family":"Elmelund","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna E.","family":"Hunt","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"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"}]},{"given":"Mark M.","family":"Smits","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"name":"Department of Internal Medicine Radboud University Medical Center  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trisha J.","family":"Grevengoed","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Christoffersen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"name":"Department of Clinical Biochemistry Rigshospitalet, University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils J.","family":"F\u00e6rgeman","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Havelund","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolai J.","family":"Wewer Albrechtsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Biochemistry Copenhagen University Hospital \u2013 Bispebjerg  Copenhagen Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-3805","authenticated-orcid":false,"given":"Jens J.","family":"Holst","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"},{"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"}]}],"member":"311","published-online":{"date-parts":[[2025,2,21]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"F24","article-title":"Effects of glucagon on glomerular filtration rate and urea and water excretion","volume":"263","author":"Ahloulay M.","year":"1992","journal-title":"The American Journal of Physiology"},{"issue":"2","key":"e_1_2_12_3_1","first-page":"F225","article-title":"Influence of glucagon on GFR and on urea and electrolyte excretion: Direct and indirect effects","volume":"269","author":"Ahloulay M.","year":"1995","journal-title":"American Journal of Physiology"},{"key":"e_1_2_12_4_1","first-page":"1240","article-title":"Effect of glucagon on the serum lipids in essential hyperlipemia and in hypercholesterolemia","volume":"11","author":"Amatuzio D. 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