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EMBO Rep. 2018 Nov 2. pii: e44706. doi: 10.15252/embr.201744706. [Epub ahead of print]

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

Author information

1
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA, Australia.
3
Faculty of Chemical and Pharmaceutical Sciences & Faculty of Medicine, Advanced Center for Chronic Diseases (ACCDiS) and Center for Exercise Metabolism and Cancer (CEMC), University of Chile, Santiago, Chile.
4
Department of Anatomy and Histology and Centre for Neuroscience, Flinders University, Adelaide, SA, Australia.
5
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
6
Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
7
Department of Chemistry, Pohang University of Science and Technology, Pohang, South Korea.
8
Children's Medical Centre, Dallas, TX, USA.
9
The Department of Physiology and Monash Biomedicine Discovery Institute, Metabolic Disease and Obesity Program, Monash University, Clayton, Vic., Australia.
10
Touchstone Diabetes Center and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
11
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Vic., Australia.
12
Department of Human Physiology and Centre for Neuroscience, Flinders University, Adelaide, SA, Australia damien.keating@flinders.edu.au beverly.rothermel@utsouthwestern.edu.
13
South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.
14
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA damien.keating@flinders.edu.au beverly.rothermel@utsouthwestern.edu.
15
Department of Molecular Biology, University of Texas Southwestern Medical Centre, Dallas, TX, USA.

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.

KEYWORDS:

Down syndrome; RCAN1; adaptive thermogenesis; obesity; sarcolipin

PMID:
30389725
DOI:
10.15252/embr.201744706

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