Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease

Ryo Ito; Shiyu Xie; Myagmar Tumenjargal; Yuto Sugahara; Chaoran Yang; Hiroki Takahashi; Makoto Arai; Shin-Ichi Inoue; Aoi Uchida; Kenji Nakano; Hyunmi Choi; Ge Yang; Yanan Zhao; Rei Yamaguchi; Hitomi Jin; Hina Sagae; Youichiro Wada; Toshiya Tanaka; Hiroshi Kimura; Tatsuhiko Kodama; Hiroyuki Aburatani; Kazuhisa Takeda; Takeshi Inagaki; Timothy F Osborne; Takeshi Yoneshiro; Yoshihiro Matsumura; Juro Sakai

doi:10.1016/j.isci.2024.109398

Mitochondrial biogenesis in white adipose tissue mediated by JMJD1A-PGC-1 axis limits age-related metabolic disease

iScience. 2024 Mar 1;27(4):109398. doi: 10.1016/j.isci.2024.109398. eCollection 2024 Apr 19.

Authors

Ryo Ito¹, Shiyu Xie¹, Myagmar Tumenjargal¹, Yuto Sugahara¹, Chaoran Yang¹, Hiroki Takahashi¹, Makoto Arai¹, Shin-Ichi Inoue¹, Aoi Uchida², Kenji Nakano¹, Hyunmi Choi¹, Ge Yang¹, Yanan Zhao¹, Rei Yamaguchi¹, Hitomi Jin¹, Hina Sagae¹, Youichiro Wada³, Toshiya Tanaka⁴, Hiroshi Kimura⁵, Tatsuhiko Kodama⁴, Hiroyuki Aburatani⁶, Kazuhisa Takeda^{1

7}, Takeshi Inagaki⁸, Timothy F Osborne⁹, Takeshi Yoneshiro¹, Yoshihiro Matsumura¹, Juro Sakai^{1

2}

Affiliations

¹ Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
² Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
³ Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan.
⁴ Department of Nuclear Receptor Medicine, Laboratories for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
⁵ Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama 226-8503, Japan.
⁶ Genome Science and Medicine Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
⁷ Graduate School of Nursing, Miyagi University, Miyagi 981-3298, Japan.
⁸ Laboratory of Epigenetics and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan.
⁹ Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, and Medicine in the Division of Endocrinology, Diabetes and Metabolism of the Johns Hopkins University School of Medicine, Petersburg, FL 33701, USA.

Abstract

Mitochondria play a vital role in non-shivering thermogenesis in both brown and subcutaneous white adipose tissues (BAT and scWAT, respectively). However, specific regulatory mechanisms driving mitochondrial function in these tissues have been unclear. Here we demonstrate that prolonged activation of β-adrenergic signaling induces epigenetic modifications in scWAT, specifically targeting the enhancers for the mitochondria master regulator genes Pgc1a/b. This is mediated at least partially through JMJD1A, a histone demethylase that in response to β-adrenergic signals, facilitates H3K9 demethylation of the Pgc1a/b enhancers, promoting mitochondrial biogenesis and the formation of beige adipocytes. Disruption of demethylation activity of JMJD1A in mice impairs activation of Pgc1a/b driven mitochondrial biogenesis and limits scWAT beiging, contributing to reduced energy expenditure, obesity, insulin resistance, and metabolic disorders. Notably, JMJD1A demethylase activity is not required for Pgc1a/b dependent thermogenic capacity of BAT especially during acute cold stress, emphasizing the importance of scWAT thermogenesis in overall energy metabolism.

Keywords: Cell biology; Cellular physiology; Pathophysiology.