TY - JOUR
T1 - Regulator of Calcineurin 1 helps coordinate whole-body metabolism and thermogenesis
AU - Rotter, David
AU - Peiris, Heshan
AU - Grinsfelder, D
AU - Martin, Alyce
AU - Burchfield, Jana
AU - Parra, Valentina
AU - Hull, Christi
AU - Morales, Cyndi
AU - Jessup, Claire
AU - Matusica, Dusan
AU - Parks, Brian
AU - Lusis, Aldons
AU - Nguyen, Ngoc
AU - Oh, Misook
AU - Iyoke, Israel
AU - Jakkampudi, Tanvi
AU - McMillan, D
AU - Sadek, Hesham
AU - Watt, Matthew
AU - Gupta, Rana
AU - Pritchard, Melanie
AU - Keating, Damien
AU - Rothermel, Beverly
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - adaptive thermogenesis
KW - Down syndrome
KW - obesity
KW - RCAN1
KW - sarcolipin
UR - http://www.scopus.com/inward/record.url?scp=85055923025&partnerID=8YFLogxK
U2 - 10.15252/embr.201744706
DO - 10.15252/embr.201744706
M3 - Article
VL - 19
JO - EMBO REPORTS
JF - EMBO REPORTS
SN - 1469-221X
IS - 12
M1 - e44706
ER -