A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling

Noriaki Shimizu, Takako Maruyama, Noritada Yoshikawa, Ryo Matsumiya, Yanxia Ma, Naoki Ito, Yuki Tasaka, Akiko Kuribara-Souta, Keishi Miyata, Yuichi Oike, Stefan Berger, Günther Schütz, Shin’ichi Takeda and Hirotoshi Tanaka ()
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Noriaki Shimizu: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Takako Maruyama: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Noritada Yoshikawa: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Ryo Matsumiya: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Yanxia Ma: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Naoki Ito: National Institute of Neuroscience, National Center of Neurology and Psychiatry
Yuki Tasaka: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Akiko Kuribara-Souta: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo
Keishi Miyata: Graduate School of Medical Sciences, Kumamoto University
Yuichi Oike: Graduate School of Medical Sciences, Kumamoto University
Stefan Berger: German Cancer Research Center
Günther Schütz: German Cancer Research Center
Shin’ichi Takeda: National Institute of Neuroscience, National Center of Neurology and Psychiatry
Hirotoshi Tanaka: IMSUT Hospital, The Institute of Medical Science, The University of Tokyo

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by the hypothalamus-pituitary-adrenal signalling axis via a glucocorticoid-driven transcriptional programme. Here we unravel the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. Metabolically, GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this skeletal muscle-liver-fat signalling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity.

Date: 2015
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DOI: 10.1038/ncomms7693

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