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Publication
Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome
mouse model.
Authors Chen F, Saqib M, Nguyen CM, Sarver DC, Yu YE, Aja S, Seldin MM, Wong GW
Submitted By Submitted Externally on 8/19/2026
Status Published
Journal eLife
Year 2026
Date Published 8/3/2026
Volume : Pages 15 : Not Specified
PubMed Reference 42544450
Abstract Gene dosage imbalance resulting from an extra copy of human chromosome 21
(Hsa21) contributes to numerous clinical features in Down syndrome (DS). 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 ~58% 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.




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