Although this was first noted in the 1960s ( Milunsky and Neurath, 1968), the underlying cause for these metabolic dysregulations is mostly unknown and largely underexplored. In addition to developmental abnormalities associated with DS, there is an increasing awareness that adolescents and adults with DS also have an increased incidence of obesity, insulin resistance, and diabetes ( Van Goor et al., 1997 Bertapelli et al., 2016 Fonseca et al., 2005). Given the significant impact of intellectual disability on the lives of individuals with DS, research emphasis has naturally focused on the neurological deficits underpinning trisomy 21 ( Potier and Reeves, 2016). Humans with trisomy 21 have cognitive deficits, altered craniofacial development, and are at significantly higher risk for congenital heart defects, hearing and vision loss, leukemia, gastrointestinal disease, and early-onset dementia ( Antonarakis et al., 2020). The increased expression of ~500 transcribed sequences of human chromosome 21 (Hsa21) affects many cell types and organ systems during development and in the postnatal period ( Korenberg et al., 1994 Antonarakis, 2017). Down syndrome (DS), resulting from trisomy of chromosome 21, is one of the rare aneuploidies compatible with life although as many as 80% of trisomy 21 conceptuses miscarry ( Antonarakis et al., 2020). The presence of an extra chromosome in mammals is generally lethal during fetal development, due to widespread cellular havoc caused by misregulated gene expression arising from gene dosage imbalance ( Zhu et al., 2018). This serendipitous discovery provides proof-of-concept that sarcolipin-mediated thermogenesis via uncoupling of the SERCA pump can be harnessed to promote energy expenditure and metabolic health. Mitochondrial respiration is also markedly increased in skeletal muscle to meet the high ATP demand created by the futile cycle and hyperactivity. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca 2+ ATPase (SERCA) activity and energy dissipation. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Chromosome Engineering Research Center, Tottori University, Japan.Division of Genome and Cellular Functions, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Japan.
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