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Nat Commun. 2015 Apr 1;6:6693. doi: 10.1038/ncomms7693.

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

Author information

1
Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
2
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
3
Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
4
Division of Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
5
1] Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan [2] Division of Rheumatology, Center for Antibody and Vaccine, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

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.

PMID:
25827749
PMCID:
PMC4396397
DOI:
10.1038/ncomms7693
[Indexed for MEDLINE]
Free PMC Article

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