{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:33:05Z","timestamp":1790249585936,"version":"4.1.0"},"reference-count":172,"publisher":"Wiley","issue":"S2","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Metabolic dysfunction\u2010associated steatotic liver disease (MASLD) arises from dysregulated interactions between nutrient delivery, adipose tissue lipid handling and liver lipid metabolism, which collectively coalesce to drive inflammatory signalling leading to metabolic dysfunction\u2010associated steatohepatitis (MASH) and fibrosis. Recent clinical success of incretin\u2010 and glucagon\u2010based therapies in both diabetes and obesity has intensified interest into how these hormonal pathways modify liver disease progression. In this review, we integrate preclinical and clinical data to examine how glucagon\u2010like peptide\u20101 (GLP\u20101), glucose\u2010dependent insulinotropic polypeptide (GIP) and glucagon engage key pathogenic nodes, including the gut\u2013liver and adipose\u2013liver axes, hepatic lipid synthesis and oxidation, mitochondrial function and nonparenchymal inflammatory responses. GLP\u20101\u2010based therapies consistently improve steatosis and steatohepatitis through reductions in nutrient flux to the liver, improved adipose tissue insulin sensitivity and weight\u2010independent anti\u2010inflammatory effects, despite limited direct action in hepatocytes. GIP signalling appears to modulate adipose tissue lipid handling and expandability, thereby limiting fatty acid spillover to the liver, although its role in hepatic inflammation remains incompletely defined. In contrast, glucagon receptor activation directly targets hepatocytes to enhance oxidative metabolism and reduce hepatocellular stress. Across studies, improvements in fibrosis appear secondary to sustained reductions in metabolic and inflammatory injury suggesting the addition of anti\u2010fibrotic combination therapies may exert further benefits. Looking ahead, a key challenge will be defining how these hormonal pathways interact within distinct metabolic states and how this greater mechanistic understanding can be leveraged to rationally combine therapies and expand the proportion of patients who respond across the MASLD spectrum.<\/jats:p>","DOI":"10.1111\/dom.70624","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T09:15:33Z","timestamp":1773306933000},"page":"31-45","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Incretin and Glucagon Signalling in\n                    <scp>MASLD<\/scp>\n                    and\n                    <scp>MASH<\/scp>\n                    : Integrating Metabolic Pathways With Disease Progression"],"prefix":"10.1111","volume":"28","author":[{"given":"Evangelia E.","family":"Tsakiridis","sequence":"first","affiliation":[{"name":"Center for Metabolism, Obesity and Diabetes Research, Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences McMaster University  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5425-8275","authenticated-orcid":false,"given":"Gregory R.","family":"Steinberg","sequence":"additional","affiliation":[{"name":"Center for Metabolism, Obesity and Diabetes Research, Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Health Sciences McMaster University  Hamilton Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"issue":"6","key":"e_1_2_8_2_1","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2025.16381","article-title":"Metabolic Dysfunction\u2010Associated Steatotic Liver Disease\u2010The New Epidemic of Chronic Liver Disease","volume":"8","author":"Gines P.","year":"2025","journal-title":"JAMA Network Open"},{"key":"e_1_2_8_3_1","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jhep.2025.02.033","article-title":"Integrative Metabolism in MASLD and MASH: Pathophysiology and Emerging Mechanisms","volume":"83","author":"Steinberg G. 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