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Hopkins Universityhttps://www.ebi.ac.uk/ena/browser/view/PRJNA877694The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model carrying a near complete human chromosome 21 (referred to as TcMAC21). Independent of diets and housing temperatures, TcMAC21 mice consume more calories and are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have higher body temperature. The hypermetabolism and elevated thermogenesis are due to sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) activity and energy dissipation. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle. Thus, sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can potentially be harnessed to promote energy expenditure, weight loss and metabolic health.xref:EuropePMC:PMC10229126xref:EuropePMC:PMC9915508ENAfalseGene expression analyses of TcMAC21 mice2023-06-032023-06-03PRJNA877694