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 Gupta; Melanie A Pritchard; Damien J Keating; Beverly A Rothermel

doi:10.15252/embr.201744706

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

EMBO Rep. 2018 Dec;19(12):e44706. doi: 10.15252/embr.201744706. Epub 2018 Nov 2.

Authors

David Rotter¹, Heshan Peiris², D Bennett Grinsfelder¹, Alyce M Martin², Jana Burchfield¹, Valentina Parra³, Christi Hull¹, Cyndi R Morales¹, Claire F Jessup⁴, Dusan Matusica⁴, Brian W Parks⁵, Aldons J Lusis⁶, Ngoc Uyen Nhi Nguyen¹, Misook Oh^{1

7}, Israel Iyoke¹, Tanvi Jakkampudi¹, D Randy McMillan^{1

8}, Hesham A Sadek¹, Matthew J Watt⁹, Rana K Gupta¹⁰, Melanie A Pritchard¹¹, Damien J Keating^{12

13}, Beverly A Rothermel^{14

15}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / cytology
Adipocytes / drug effects
Adipocytes / metabolism
Adipose Tissue / metabolism
Adipose Tissue, Beige / drug effects
Adipose Tissue, Beige / metabolism
Adipose Tissue, White / drug effects
Adipose Tissue, White / metabolism
Adrenergic Agents / pharmacology
Animals
Calcineurin / metabolism
Calcium-Binding Proteins
Cell Differentiation / drug effects
Cold Temperature
Female
Insulin Resistance
Intracellular Signaling Peptides and Proteins / deficiency
Intracellular Signaling Peptides and Proteins / metabolism*
Lipid Metabolism / drug effects
Liver / metabolism
Male
Metabolic Syndrome / metabolism
Metabolism* / drug effects
Mice
Mice, Knockout
Muscle Proteins / deficiency
Muscle Proteins / genetics
Muscle Proteins / metabolism*
Muscle, Skeletal / metabolism
Muscle, Striated / metabolism
Obesity / metabolism
Obesity / pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
Promoter Regions, Genetic / genetics
Proteolipids / genetics
Proteolipids / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Thermogenesis* / drug effects
Uncoupling Protein 1 / metabolism

Substances

Adrenergic Agents
Calcium-Binding Proteins
DSCR1 protein, mouse
Intracellular Signaling Peptides and Proteins
Muscle Proteins
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Proteolipids
RNA, Messenger
Uncoupling Protein 1
sarcolipin
Calcineurin

Abstract

Publication types

MeSH terms

Substances

Grants and funding