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Dysregulated systemic metabolism in a Down syndrome mouse model
Dylan C Sarver1, Cheng Xu1, Leandro M Velez2
1Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Molecular Metabolism
|January 1, 2023
Summary
Gene dosage imbalance in Down syndrome (DS) affects metabolism. Trisomy 21 mouse models show altered energy expenditure and glucose intolerance, with diet-induced obesity exacerbating dyslipidemia and insulin sensitivity issues.
Area of Science:
- Genetics and Metabolism
- Aneuploidy Research
- Down Syndrome (DS) Pathophysiology
Background:
- Trisomy 21 (Down syndrome) causes gene dosage imbalance, impacting multiple organ systems.
- While CNS effects are well-studied, the impact of aneuploidy on whole-body metabolism remains less understood.
- Obesity, diabetes, and related conditions are prevalent in individuals with Down syndrome.
Purpose of the Study:
- To systematically analyze key metabolic parameters in a mouse model of Down syndrome (Ts65Dn mice).
- To investigate the effects of gene dosage imbalance on metabolism under basal and obesity-inducing conditions.
- To explore the molecular mechanisms underlying metabolic dysregulation in trisomy 21.
Main Methods:
- Comprehensive metabolic phenotyping of Ts65Dn mice and euploid littermates.
- High-fat diet (HFD) challenge to induce obesity.
- RNA sequencing of liver, skeletal muscle, and adipose tissues.
- Pathway enrichment and gene-centrality analyses to identify regulatory mechanisms.
Main Results:
- Chow-fed Ts65Dn mice exhibited increased energy expenditure, reduced cholesterol, and mild glucose intolerance.
- HFD challenge revealed sexually dimorphic metabolic deterioration, including dyslipidemia in both sexes.
- Male Ts65Dn mice showed impaired insulin sensitivity, reduced mitochondrial activity, and increased liver/adipose inflammation and fibrosis.
Conclusions:
- Altered expression of both trisomic and disomic genes in peripheral tissues contributes to metabolic dysfunction.
- These findings provide a foundation for understanding aneuploidy's impact on in vivo metabolism.
- Identified conserved pathways and potential endocrine drivers of adipose-liver crosstalk in metabolic dysregulation.
