Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis

David Rotter, Heshan Peiris, D. Bennett Grinsfelder, Alyce M. Martin, Jana Burchfield, Valentina Parra, Christi Hull, Cyndi R. Morales, Claire F. Jessup, Dusan Matusica, Brian W. Parks, Aldons J. Lusis, Ngoc Uyen Nhi Nguyen, Misook Oh, Israel Iyoke, Tanvi Jakkampudi, D. Randy McMillan, Hesham A Sadek, Matthew J. Watt, Rana K GuptaMelanie A. Pritchard, Damien J. Keating, Beverly A Rothermel

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Increasing non-shivering thermogenesis (NST), which expends calories as heat rather than storing them as fat, is championed as an effective way to combat obesity and metabolic disease. Innate mechanisms constraining the capacity for NST present a fundamental limitation to this approach, yet are not well understood. Here, we provide evidence that Regulator of Calcineurin 1 (RCAN1), a feedback inhibitor of the calcium-activated protein phosphatase calcineurin (CN), acts to suppress two distinctly different mechanisms of non-shivering thermogenesis (NST): one involving the activation of UCP1 expression in white adipose tissue, the other mediated by sarcolipin (SLN) in skeletal muscle. UCP1 generates heat at the expense of reducing ATP production, whereas SLN increases ATP consumption to generate heat. Gene expression profiles demonstrate a high correlation between Rcan1 expression and metabolic syndrome. On an evolutionary timescale, in the context of limited food resources, systemic suppression of prolonged NST by RCAN1 might have been beneficial; however, in the face of caloric abundance, RCAN1-mediated suppression of these adaptive avenues of energy expenditure may now contribute to the growing epidemic of obesity.

Original languageEnglish (US)
Article numbere44706
JournalEMBO Reports
Volume19
Issue number12
DOIs
StatePublished - Dec 2018

Keywords

  • Down syndrome
  • RCAN1
  • adaptive thermogenesis
  • obesity
  • sarcolipin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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    Rotter, D., Peiris, H., Grinsfelder, D. B., Martin, A. M., Burchfield, J., Parra, V., Hull, C., Morales, C. R., Jessup, C. F., Matusica, D., Parks, B. W., Lusis, A. J., Nguyen, N. U. N., Oh, M., Iyoke, I., Jakkampudi, T., McMillan, D. R., Sadek, H. A., Watt, M. J., ... Rothermel, B. A. (2018). Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis. EMBO Reports, 19(12), [e44706]. https://doi.org/10.15252/embr.201744706