Cargando…

UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

Uncoupling Protein 1 (UCP1) plays a central role in non-shivering 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 Ca(2+) cycling by sarco/endoplasmic reticulum...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727902/
https://www.ncbi.nlm.nih.gov/pubmed/29131158
http://dx.doi.org/10.1038/nm.4429
Descripción
Sumario:Uncoupling Protein 1 (UCP1) plays a central role in non-shivering 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 Ca(2+) cycling by sarco/endoplasmic reticulum Ca(2+)-ATPase2b (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 Ca(2+) cycling by the activation of α1/β3-adrenergic receptors or the SERCA2b-RyR2 pathway stimulates UCP1-independent thermogenesis. In the absence of UCP1, beige fat dynamically expends glucose through enhanced glycolysis, tricarboxylic acid metabolism, and pyruvate dehydrogenase activity for ATP-dependent thermogenesis by the SERCA2b pathway; beige fat thereby functions as a “glucose-sink” and improves glucose tolerance independent of body-weight loss. Our study uncovers a non-canonical thermogenic mechanism by which beige fat controls whole-body energy homeostasis through Ca(2+) cycling.