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While dysregulated metabolism has long been noted in DS, the underlying cause is poorly understood and vastly understudied. To fill this critical knowledge gap, we conducted a comprehensive metabolic analysis of Dp(16)1Yey\/+ mice (abbreviated Dp16), a segmental duplication model carrying \u223c58% of the triplicated Hsa21 gene orthologs. Our multi-tissue transcriptomic analyses reveal shared and sex-specific increases in expression dosage of the triplicated genes in white and brown adipose tissues, liver, skeletal muscle, and hypothalamus. Despite sexual dimorphism in body weight, body temperature, food intake, and physical activity, Dp16 males and females share striking core phenotypes of pronounced insulin resistance, glucose intolerance, impaired lipid clearance, and dyslipidemia. Functional assessments, combined with biochemical, transcriptomic, and metabolomic analyses reveal tissue signatures of immune activation and a pro-inflammatory state, ER and oxidative stress, fibrosis, impaired glucose and fatty acid catabolism, altered lipid and bile acid profiles, and reduced mitochondrial respiratory capacity in Dp16 mice. These concerted changes disrupt homeostatic mechanisms that underpin metabolic health, contributing to systemic metabolic dysfunction. An obesogenic diet further exacerbates insulin resistance in Dp16 males and females despite divergent weight gain. The collective phenotypes broadly reflect the metabolic profile of DS. Our extensive molecular, biochemical, and physiological data provide an essential foundation for genetic dissection of dosage-sensitive genes affecting glucose and lipid metabolism, and for testing therapeutic strategies to improve metabolic outcomes in DS.<\/jats:p>","DOI":"10.64898\/2026.01.13.699318","type":"posted-content","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T11:00:22Z","timestamp":1768388422000},"source":"Crossref","is-referenced-by-count":1,"title":["Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome mouse model"],"prefix":"10.64898","author":[{"given":"Fangluo","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muzna","family":"Saqib","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy M.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, University of California, Irvine, Irvine, USA"},{"name":"Center for Epigenetics and Metabolism, University of California Irvine, Irvine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan C.","family":"Sarver","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA"},{"name":"Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. 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