title: A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling.
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.
authors.affiliation: 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.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: 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.
authors.forename: Takako
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: 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.
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.affiliation: 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.
authors.forename: Ryo
authors.initials: R
authors.lastname: Matsumiya
authors.affiliation: 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.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ito
authors.affiliation: 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.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tasaka
authors.affiliation: 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.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuribara-Souta
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto 860-8556, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Berger
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1, Ogawa-higashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: 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.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000378:metabolism*; D000409:Alanine / Q000097:blood; D000818:Animals; D004734:Energy Metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006984:Hypertrophy; D008066:Lipolysis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D059748:Proteolysis; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C575863:NR3C1 protein, mouse; D011965:Receptors, Glucocorticoid; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000409:Alanine
references.citation: Lancet. 2006 May 13;367(9522):1605-17
references.pmid: 16698415
references.citation: Nat Med. 2005 Apr;11(4):400-8
references.pmid: 15778720
references.citation: Cell Metab. 2007 Jun;5(6):415-25
references.pmid: 17550777
references.citation: Cell Metab. 2007 Jun;5(6):426-37
references.pmid: 17550778
references.citation: Cell Metab. 2011 Feb 2;13(2):170-82
references.pmid: 21284984
references.citation: Genes Dev. 2012 Feb 1;26(3):271-81
references.pmid: 22302939
references.citation: Cell. 2012 Feb 3;148(3):556-67
references.pmid: 22304921
references.citation: Cell Metab. 2012 Mar 7;15(3):311-23
references.pmid: 22405069
references.citation: Biochem J. 2012 Apr 1;443(1):165-71
references.pmid: 22233381
references.citation: Cell Metab. 2014 Sep 2;20(3):512-25
references.pmid: 25043817
references.citation: Nature. 2014 Sep 18;513(7518):436-9
references.pmid: 25043058
references.citation: Cell Metab. 2014 Oct 7;20(4):670-7
references.pmid: 25130400
references.citation: Nat Med. 2013 Jan;19(1):83-92
references.pmid: 23202295
references.citation: Cell Metab. 2012 Sep 5;16(3):387-93
references.pmid: 22958921
references.citation: J Biol Chem. 2014 Oct 24;289(43):29751-65
references.pmid: 25170079
references.citation: Cell Metab. 2013 Feb 5;17(2):162-84
references.pmid: 23395166
references.citation: Biochimie. 2013 Apr;95(4):692-9
references.pmid: 23123503
references.citation: Metabolism. 2013 Jul;62(7):889-97
references.pmid: 23357530
references.citation: Nat Med. 2012 Aug;18(8):1279-85
references.pmid: 22842477
references.citation: Nat Commun. 2013;4:2316
references.pmid: 23939267
references.citation: Int J Biochem Cell Biol. 2013 Oct;45(10):2163-72
references.pmid: 23806868
references.citation: Mol Cell Endocrinol. 2013 Nov 5;380(1-2):79-88
references.pmid: 23523565
references.citation: Handb Clin Neurol. 2014;120:749-71
references.pmid: 24365350
references.citation: Cell Metab. 2014 Jan 7;19(1):96-108
references.pmid: 24411942
references.citation: Dev Dyn. 2014 Feb;243(2):201-15
references.pmid: 24038488
references.citation: Diabetologia. 2014 May;57(5):860-7
references.pmid: 24619218
references.citation: Nat Med. 2014 Jun;20(6):664-9
references.pmid: 24813250
references.citation: Cell. 2014 Jul 3;158(1):41-53
references.pmid: 24995977
references.citation: Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):11592-9
references.pmid: 25082895
references.citation: J Clin Invest. 2014 Sep;124(9):3913-22
references.pmid: 25133427
references.citation: Diabetes. 2002 Jun;51(6):1889-95
references.pmid: 12031978
references.citation: J Clin Invest. 1972 Jun;51(6):1440-9
references.pmid: 5024041
references.citation: Metabolism. 1973 Feb;22(2):179-207
references.pmid: 4567003
references.citation: J Clin Invest. 1990 Nov;86(5):1423-7
references.pmid: 2243122
references.citation: Nat Genet. 1999 Sep;23(1):99-103
references.pmid: 10471508
references.citation: Nucleic Acids Res. 1999 Oct 1;27(19):e27
references.pmid: 10481039
references.citation: J Clin Endocrinol Metab. 2006 Nov;91(11):4287-94
references.pmid: 16912127