Activin E Controls Energy Homeostasis in Both Brown and White Adipose Tissues as a Hepatokine

Osamu Hashimoto,Masayuki Funaba,Kazunari Sekiyama,Satoru Doi,Daichi Shindo,Ryo Satoh,Hiroshi Itoi,Hiroaki Oiwa,Masahiro Morita,Chisato Suzuki,Makoto Sugiyama,Norio Yamakawa,Hitomi Takada,Shigenobu Matsumura,Kazuo Inoue,Seiichi Oyadomari,Hiromu Sugino,Akira Kurisaki

doi:10.1016/j.celrep.2018.10.008

Abstract

Brown adipocyte activation or beige adipocyte emergence in white adipose tissue (WAT) increases energy expenditure, leading to a reduction in body fat mass and improved glucose metabolism. We found that activin E functions as a hepatokine that enhances thermogenesis in response to cold exposure through beige adipocyte emergence in inguinal WAT (ingWAT). Hepatic activin E overexpression activated thermogenesis through Ucp1 upregulation in ingWAT and other adipose tissues including interscapular brown adipose tissue and mesenteric WAT. Hepatic activin E-transgenic mice exhibited improved insulin sensitivity. Inhibin βE gene silencing inhibited cold-induced Ucp1 induction in ingWAT. Furthermore, invitro experiments suggested that activin Edirectly stimulated expression of Ucp1 and Fgf21,which was mediated by transforming growth factor-β or activin type I receptors. We uncovered a function of activin E to stimulate energy expenditure through brown and beige adipocyte activation, suggesting a possible preventive or therapeutic target for obesity.

Highlights

Adipose tissue plays a vital role in regulation of whole-body energy metabolism
Improvement of Insulin Sensitivity in Transgenic Mice Overexpressing Hepatic Activin E Previous reports have described fluctuation of activin E (Inhbe) mRNA expression in the rodent liver according to the nutritional status such as fasting, feeding, or chronic high calorie intake (Rodgarkia-Dara et al, 2006; Hashimoto et al, 2009)
The epididymal White adipose tissue (WAT) weight was significantly decreased in Alb-ActE mice fed the high-fat diet (Figure 1F)

Summary

Introduction

Adipose tissue plays a vital role in regulation of whole-body energy metabolism. White adipose tissue (WAT) functions as an energy storage depot, whereas brown adipose tissue (BAT) is an energy dissipation depot. White adipocytes have a unilocular lipid droplet, and brown adipocytes are characterized by multilocular lipid droplets, densely packed mitochondria, and unique expression of uncoupling protein 1 (Ucp). Norepinephrine secreted by sympathetic nerves activates brown and beige adipocytes via b-adrenergic receptors, resulting in acceleration of lipolysis and upregulation of Ucp expression (Cousin et al, 1992; Wu et al, 2012). Identification of non-sympathetic regulators of brown and beige adipocyte activity has attracted great interest (Cereijo et al, 2015). Several factors, such as Fgf, Bmp8b, and Irisin, have been shown to regulate brown and beige adipogenesis and activation of brown and beige adipocytes (Harms and Seale 2013)

Results

Discussion

Conclusion