Hypermetabolism in mice carrying a near-complete human chromosome 21
Dylan C Sarver,
Cheng Xu,
Susana Rodriguez,
Susan Aja,
Andrew E Jaffe,
Feng J Gao,
Michael Delannoy,
Muthu Periasamy,
Yasuhiro Kazuki,
Mitsuo Oshimura,
Roger H Reeves,
G William Wong
Affiliations
Dylan C Sarver
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, United States
Cheng Xu
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, United States
Susana Rodriguez
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, United States
Susan Aja
Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
Andrew E Jaffe
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States; The Lieber Institute for Brain Development, Baltimore, United States; Center for Computational Biology, Johns Hopkins University, Baltimore, United States; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
Feng J Gao
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States
Michael Delannoy
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States
Muthu Periasamy
Department of Physiology and Cell Biology, The Ohio State University, Columbus, United States; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, United States
Division of Genome and Cellular Functions, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Tottori, Japan; Chromosome Engineering Research Center, Tottori University, Tottori, Japan
Mitsuo Oshimura
Chromosome Engineering Research Center, Tottori University, Tottori, Japan
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, United States; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, United States
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 likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca2+ 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 and hyperactivity. 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.
