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Male C57BL\/6J mice were fed HFD from 10 to 25\u2009weeks of age, then maintained on HFD or fed HFD with 80% reduced methionine (HFD\u2010MetR) for 3, 5, or 10\u2009days. Blood, liver, adipose tissue, and aortae underwent phenotypic assessment, proteomics, and metabolomics. HFD\u2010MetR induced rapid weight loss and robust metabolic improvement within 10\u2009days. Significant reductions in body weight, circulating triglycerides, glucose, insulin, adipokines and hepatokines reflected metabolic health. Proteomics revealed enriched metabolic signatures in perivascular adipose tissue (PVAT) and structural remodeling signatures in aorta. Metabolomics identified a cardioprotective signature in blood plasma, and activated mitochondrial activity and energy production in liver and brown adipose tissue. HFD\u2010MetR reversed metabolic dysfunction, and novel proteomic and metabolomic signatures were identified. Multi\u2010organ molecular changes in lipid metabolism, mitochondrial function, and bioenergetics are predicted to impact adipose tissue and liver function and cardiovascular health. Our identification of rapid changes in protein and metabolite signatures with accelerated restoration of metabolic health can be leveraged to evaluate biomarkers of metabolic health and disease in a translational context.<\/jats:p>","DOI":"10.14814\/phy2.70405","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T10:48:58Z","timestamp":1750157338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Short\u2010term dietary methionine restriction with high fat diet counteracts metabolic dysfunction in male mice"],"prefix":"10.14814","volume":"13","author":[{"given":"Marissa I.","family":"McGilvrey","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine, MaineHealth Institute for Research  Scarborough Maine USA"},{"name":"Graduate School of Biomedical Science and Engineering, University of Maine  Orono Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany","family":"Fortier","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, MaineHealth Institute for Research  Scarborough Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Cooke","sequence":"additional","affiliation":[{"name":"Orentreich Foundation for the Advancement of Science, Inc.  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