UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro, Joao Paulo Camporez, Hiroko Maki, Mayu Homma, Kosaku Shinoda, Yong Chen, Xiaodan Lu, Pema Maretich, Kazuki Tajima, Kolapo M. Ajuwon, Tomoyoshi Soga, Shingo Kajimura

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca22+ cycling by sarco/endoplasmic reticulum Ca22+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca22+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca22+ cycling.

Original languageEnglish (US)
Pages (from-to)1454-1465
Number of pages12
JournalNature Medicine
Volume23
Issue number12
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Thermogenesis
Homeostasis
Fats
Calcium
Glucose
Endoplasmic Reticulum
Adenosine Triphosphatases
Ryanodine Receptor Calcium Release Channel
Proteins
Tricarboxylic Acids
Adenosine Triphosphate
Brown Adipose Tissue
Glycolysis
Pyruvic Acid
Adrenergic Receptors
Beige Adipose Tissue
Uncoupling Protein 1
Weight Loss
Metabolism
Oxidoreductases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ikeda, K., Kang, Q., Yoneshiro, T., Camporez, J. P., Maki, H., Homma, M., ... Kajimura, S. (2017). UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nature Medicine, 23(12), 1454-1465. https://doi.org/10.1038/nm.4429

UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. / Ikeda, Kenji; Kang, Qianqian; Yoneshiro, Takeshi; Camporez, Joao Paulo; Maki, Hiroko; Homma, Mayu; Shinoda, Kosaku; Chen, Yong; Lu, Xiaodan; Maretich, Pema; Tajima, Kazuki; Ajuwon, Kolapo M.; Soga, Tomoyoshi; Kajimura, Shingo.

In: Nature Medicine, Vol. 23, No. 12, 01.01.2017, p. 1454-1465.

Research output: Contribution to journalArticle

Ikeda, K, Kang, Q, Yoneshiro, T, Camporez, JP, Maki, H, Homma, M, Shinoda, K, Chen, Y, Lu, X, Maretich, P, Tajima, K, Ajuwon, KM, Soga, T & Kajimura, S 2017, 'UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis', Nature Medicine, vol. 23, no. 12, pp. 1454-1465. https://doi.org/10.1038/nm.4429
Ikeda, Kenji ; Kang, Qianqian ; Yoneshiro, Takeshi ; Camporez, Joao Paulo ; Maki, Hiroko ; Homma, Mayu ; Shinoda, Kosaku ; Chen, Yong ; Lu, Xiaodan ; Maretich, Pema ; Tajima, Kazuki ; Ajuwon, Kolapo M. ; Soga, Tomoyoshi ; Kajimura, Shingo. / UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. In: Nature Medicine. 2017 ; Vol. 23, No. 12. pp. 1454-1465.
@article{fa5c005d54d345bfb34ed3f66badd2ed,
title = "UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis",
abstract = "Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca22+ cycling by sarco/endoplasmic reticulum Ca22+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca22+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca22+ cycling.",
author = "Kenji Ikeda and Qianqian Kang and Takeshi Yoneshiro and Camporez, {Joao Paulo} and Hiroko Maki and Mayu Homma and Kosaku Shinoda and Yong Chen and Xiaodan Lu and Pema Maretich and Kazuki Tajima and Ajuwon, {Kolapo M.} and Tomoyoshi Soga and Shingo Kajimura",
year = "2017",
month = "1",
day = "1",
doi = "10.1038/nm.4429",
language = "English (US)",
volume = "23",
pages = "1454--1465",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - UCP1-independent signaling involving SERCA2bmediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

AU - Ikeda, Kenji

AU - Kang, Qianqian

AU - Yoneshiro, Takeshi

AU - Camporez, Joao Paulo

AU - Maki, Hiroko

AU - Homma, Mayu

AU - Shinoda, Kosaku

AU - Chen, Yong

AU - Lu, Xiaodan

AU - Maretich, Pema

AU - Tajima, Kazuki

AU - Ajuwon, Kolapo M.

AU - Soga, Tomoyoshi

AU - Kajimura, Shingo

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca22+ cycling by sarco/endoplasmic reticulum Ca22+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca22+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca22+ cycling.

AB - Uncoupling protein 1 (UCP1) plays a central role in nonshivering thermogenesis in brown fat; however, its role in beige fat remains unclear. Here we report a robust UCP1-independent thermogenic mechanism in beige fat that involves enhanced ATP-dependent Ca22+ cycling by sarco/endoplasmic reticulum Ca22+-ATPase 2b (SERCA2b) and ryanodine receptor 2 (RyR2). Inhibition of SERCA2b impairs UCP1-independent beige fat thermogenesis in humans and mice as well as in pigs, a species that lacks a functional UCP1 protein. Conversely, enhanced Ca22+ cycling by activation of α1- and/or β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis in beige adipocytes. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism and pyruvate dehydrogenase activity for ATP-dependent thermogenesis through the SERCA2b pathway; beige fat thereby functions as a 'glucose sink' and improves glucose tolerance independently of body weight loss. Our study uncovers a noncanonical thermogenic mechanism through which beige fat controls whole-body energy homeostasis via Ca22+ cycling.

UR - http://www.scopus.com/inward/record.url?scp=85039073107&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039073107&partnerID=8YFLogxK

U2 - 10.1038/nm.4429

DO - 10.1038/nm.4429

M3 - Article

C2 - 29131158

AN - SCOPUS:85039073107

VL - 23

SP - 1454

EP - 1465

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 12

ER -