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Deleterious changes in cardiac metabolism are central to HFpEF pathophysiology, and proposed treatments for the disease have focused on repairing these defects. In the present study, we used a preclinical mouse model that recapitulates cardiometabolic HFpEF to elucidate the molecular mechanisms driving cardiac dysfunction and tested whether recombinant adropin (Adr.) (a liver- and brain-derived endogenous peptide hormone) could reverse observed defects. We show that long-term treatment with Adr. reversed multiple markers of HFpEF-related cardiac dysfunction (including fibrosis, diastolic dysfunction, and cardiomyocyte hypertrophy). Using untargeted metabolomics, we found that Adr. treatment reduced hexosamine biosynthesis pathway activity, leading to a reduction in the O-GlcNAcylation of the cardiac fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD). Reducing LCAD O-GlcNAcylation increased LCAD activity in vitro and reduced the accumulation of long-chain acylcarnitines in HFpEF mouse hearts in vivo. Our results suggest that Adr. may restore cardiac metabolic function in HFpEF and that targeting this pathway may be a novel therapeutic avenue for this disease.<\/jats:p>","DOI":"10.1042\/cs20261501","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:15:40Z","timestamp":1781194540000},"page":"1399-1414","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Adropin protects against cardiac remodeling and metabolic dysfunction in a male mouse HFpEF model"],"prefix":"10.1042","volume":"140","author":[{"given":"Bellina\u00a0A.S.","family":"Mushala","sequence":"first","affiliation":[{"name":"1Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."},{"name":"2Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."},{"name":"3Division of Cardiology, University of Pittsburgh, Pittsburgh, PA 15261, 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U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha","family":"Bhattarai","sequence":"additional","affiliation":[{"name":"1Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."},{"name":"2Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."},{"name":"3Division of Cardiology, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"McMahon","sequence":"additional","affiliation":[{"name":"1Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Vandevender","sequence":"additional","affiliation":[{"name":"2Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA 15261, U.S.A."},{"name":"4Division of Endocrinology and Metabolism, University of Pittsburgh, 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