Hypermetabolism in mice carrying a near complete human chromosome 21.
Dylan C SarverCheng XuSusana RodriguezSusan AjaAndrew E JaffeFeng J GaoMichael DelannoyMuthu PeriasamyYasuhiro KazukiMitsuo OshimuraRoger H ReevesG William WongPublished in: bioRxiv : the preprint server for biology (2023)
The 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 (TcMAC21) carrying a near complete human chromosome 21. 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. 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. 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.
Keyphrases
- skeletal muscle
- endothelial cells
- adipose tissue
- mouse model
- insulin resistance
- high fat diet induced
- type diabetes
- healthcare
- public health
- induced pluripotent stem cells
- small molecule
- pluripotent stem cells
- endoplasmic reticulum
- copy number
- single cell
- weight loss
- stem cells
- mental illness
- nitric oxide
- circulating tumor
- body composition
- high throughput
- cell free
- genome wide
- wild type