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Effects on appetite and body weight, as well as glucose, pyruvate and insulin tolerance, circulating lipids, liver transaminases and triglyceride content, indirect calorimetry measurements and pancreatic morphology were then examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ELA, and particularly ELA-Lys\n                      <jats:sup>12<\/jats:sup>\n                      (\u03b3GluPal), reduced food intake, circulating glucose and HbA\n                      <jats:sub>1c<\/jats:sub>\n                      concentrations relative to saline-treated HFF control mice. ELA-Lys\n                      <jats:sup>12<\/jats:sup>\n                      (\u03b3GluPal) substantially reduced blood glucose concentrations during glucose and pyruvate tolerance tests. These positive effects were largely independent of alterations in circulating insulin. However, circulating triglyceride and LDL-cholesterol concentrations were lowered, accompanied by complete normalisation of hepatic triglyceride and aminotransferase levels in all GLP-1\/apelin hybrid-treated HFF mice. Assessment of indirect calorimetry demonstrated restoration of metabolic flexibility in mice treated with ELA-Lys\n                      <jats:sup>12<\/jats:sup>\n                      (\u03b3GluPal), despite reductions in energy expenditure. Notably, GLP-1\/apelin hybrid treatment did not affect locomotor activity, whereas liraglutide treatment was associated with marked reductions in physical activity. Histological assessment of pancreatic islets revealed that all treatment modalities induced a marked enhancement of beta cell proliferative frequency, and accompanying suppression of apoptotic rates, without major alterations in islet or beta cell areas.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>\n                      Chronic administration of ELA, and especially ELA-Lys\n                      <jats:sup>12<\/jats:sup>\n                      (\u03b3GluPal), delivered pronounced metabolic improvements in HFF mice, with the clearest differences from liraglutide treatment evident in circulating lipids and hepatic biomarkers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06863-7","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:11:05Z","timestamp":1789729865000},"page":"3654-3666","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unimolecular GLP-1\/APJ receptor co-agonism improves metabolism and dyslipidaemia as well as normalising hepatic triglyceride and aminotransferase elevation in high-fat-fed mice"],"prefix":"10.1007","volume":"69","author":[{"given":"Ananyaa","family":"Sridhar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan S.","family":"Palmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Craig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Tanday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finbarr P. 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