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Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS.

Ts65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal chow-fed state and the pathophysiological state of obesity induced by a high-fat diet HFD.

RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism. Under the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance.