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PhysiologyeLife
Peer-reviewed journal article

Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome mouse model

Fangluo CheniD, Muzna Saqib, Christy M NguyeniD, Dylan C. SarveriD, Yuejin Eugene Yu, Susan M. Aja, Marcus Michael SeldiniD, Guang William WongiD

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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In-depth summary

✦ Multi-agent verified full-text synthesis

Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 3 (1 Jul 2026) · CC BY 4.0

Dp16 mice, carrying 115 triplicated Hsa21 orthologs, show sex-shared insulin resistance, glucose intolerance and dyslipidemia, worsened by high-fat diet, with multi-tissue transcriptome and metabolome signatures.

Metabolic dysfunction in Down syndrome has been recognized for decades, but its cause is poorly understood. Ts65Dn carries 41 extra non-Hsa21 genes and TcMAC21 is hypermetabolic, so Dp16, with 115 mouse-origin triplicated orthologs and no extra genes, can isolate the effect of gene dosage.

Key results

  1. ShownOn standard chow, Dp16 males and females share fasting hyperinsulinemia, impaired glucose and insulin tolerance, and impaired triglyceride clearance, despite sex-divergent body weight, food intake and body temperature.

    Fasting insulin higher in both sexes; GTT, ITT and lipid tolerance test impaired in both. Fasting/GTT/ITT n: males WT 15 vs Dp16 12; females WT 14 vs Dp16 15. Two-way ANOVA with Sidek post hoc. · Sexual dimorphism in body weight, food intake…; Figure legends

  2. ShownA high-fat diet worsens glucose intolerance and insulin resistance in both sexes even though Dp16 males gain less weight than WT; pooled-serum FPLC profiles suggest higher VLDL-TG and lower LDL-C.

    Males diverge from WT in body weight from six weeks on HFD; GTT worse and ITT glucose clearance reduced in both sexes (females more pronounced). Male WT 15 vs Dp16 12; female WT 14 vs Dp16 14. · Sexually dimorphic response of Dp16 mice to an…; High-fat diet exacerbates glucose intolerance…; Figure legends

  3. ShownMost triplicated Hsa21 orthologs are expressed at the expected higher dosage across metabolic tissues, with tissue- and sex-specific patterns and little dosage compensation, except in female gWAT.

    Majority of the 115 triplicated genes at 1.5-fold or higher in bulk RNA-seq; female gWAT is the only tissue with 8 triplicated orthologs significantly suppressed; n = 6 per genotype per sex per tissue. · Increased gene expression dosage of the…; Figure legends

  4. ShownUntargeted metabolomics shows large, mostly sex-specific remodeling of liver and serum, including altered bile acids, acylcarnitines, eicosanoids and phospholipids.

    4182 metabolites in 48 samples (n = 6 per genotype per sex). Differential metabolites: 319 male liver, 337 female liver, 422 male serum, 835 female serum; 32 shared in liver and 155 in serum between sexes. · Altered hepatic and serum metabolome in Dp16…; Untargeted serum and liver metabolomic analyses

  5. SuggestedTranscriptomes indicate immune activation, fibrosis, ER stress and reduced respiration and lipid metabolism, with female-biased DEG counts; biochemical fibrosis and oxidative stress markers only partly agree.

    DEG threshold padj < 0.05 and log2(FC) > 0.5, n = 6 per genotype per tissue; females have more DEGs than males except in liver. Hydroxyproline higher in female liver; MDA higher in male liver; BAT respiratory capacity reduced in both sexes. · Transcriptomic signatures of immune activation…; Sexual dimorphism in body weight, food intake…; RNA-sequencing and bioinformatics analysis

Methods, data and reproducibility

Chow- and high-fat-fed Dp16 and wild-type littermates of both sexes were phenotyped by indirect calorimetry and glucose, insulin and lipid tolerance tests, then profiled by bulk RNA-seq (six tissues), untargeted LC-MS/MS metabolomics of liver and serum, and tissue biochemistry.

  • Bulk RNA-seq of liver, gWAT, iWAT, BAT, gastrocnemius and hypothalamus from chow-fed Dp16 and WT mice (27.5 weeks old) · Mus musculus (mouse) · n = n = 6 per genotype per sex per tissue; one Dp16 female gWAT excluded · PRJNA1160420
  • Untargeted LC-MS/MS metabolomics of liver and serum, Dp16 vs WT, both sexes · Mus musculus (mouse) · n = n = 6 per genotype per sex; 48 samples · ST004905, ST004915, ST004916, ST004918; DOI 10.21228/M8SZ8Q
  • Chow-fed fasting insulin, glucose tolerance and insulin tolerance cohorts · Mus musculus (mouse) · n = Males WT 15, Dp16 12; females WT 14, Dp16 15
  • High-fat-diet fasting, glucose tolerance and insulin tolerance cohorts · Mus musculus (mouse) · n = Males WT 15, Dp16 12; females WT 14, Dp16 14
  • Chow-fed tissue weights at termination · Mus musculus (mouse) · n = WT male 10; Dp16 male 30; WT female 15; Dp16 female 10
Methods & tools
DESeq2, Fastp, Hisat2, FeatureCounts, ClusterProfiler, XCMS, ProteoWizard, PLS-DA, CLAMS indirect calorimetry, Echo-MRI body composition, Seahorse respirometry, GraphPad Prism 10
Data & accessions
https://www.metabolomicsworkbench.org/http://dx.doi.org/10.21228/M8SZ8Q
Reagents & environment
GRCm39/mm39 reference genome; CLAMS software version 5.18; GraphPad Prism 10 for statistics and plots.
Reproducibility gaps
No analysis code is released; RNA-seq and metabolomics were processed with outsourced in-house vendor pipelines. Sample sizes vary between assays.
Limitations (5)
  • Dp16 carries only about 58% of Hsa21 gene orthologs, so it does not model the full complement of triplicated genes. · stated by the authors
  • Dp16 is a segmental duplication, not an independently segregating trisomy, so dosage effects cannot be separated from effects of an extra chromosome. · stated by the authors
  • Transcript changes may not translate to protein changes (no proteomics). Pancreatic insulin content was not measured and no pancreas RNA-seq passed quality control. · stated by the authors
  • Claims that dosage is the primary cause rest on associations; no triplicated gene was normalized or rescued, and sex hormones are possible confounders. · noted in this summary
  • Group sizes are unbalanced across assays (for example, 5-6 female Dp16 vs 13-15 WT in calorimetry; 30 vs 10 male Dp16 vs WT in tissue weights), limiting sex-by-genotype comparisons. · noted in this summary

Who should read:Read this if you study Down syndrome mouse models, sex differences in metabolism, or need multi-tissue transcriptome and metabolome resources for dissecting dosage-sensitive genes.

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