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

doi:10.1101/2023.01.30.526183

Hypermetabolism in mice carrying a near complete human chromosome 21

bioRxiv [Preprint]. 2023 Jan 31:2023.01.30.526183. doi: 10.1101/2023.01.30.526183.

Authors

Dylan C Sarver^{1

2}, Cheng Xu^{1

2}, Susana Rodriguez^{1

2}, Susan Aja^{2

3}, Andrew E Jaffe^{4

5

6

7

8

9}, Feng J Gao¹, Michael Delannoy¹⁰, Muthu Periasamy^{11

12}, Yasuhiro Kazuki^{13

14}, Mitsuo Oshimura¹⁴, Roger H Reeves^{1

8}, G William Wong^{1

2}

Affiliations

¹ Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
² Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
³ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁶ The Lieber Institute for Brain Development, Baltimore, MD, USA.
⁷ Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.
¹² Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.
¹³ Division of Genome and Cellular Functions, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Tottori, Japan.
¹⁴ Chromosome Engineering Research Center, Tottori University, Tottori, Japan.

Abstract

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.

Publication types

Preprint