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ResearchIn-Press PreviewEndocrinologyMuscle biology Open Access | 10.1172/jci.insight.162382

The crucial role of muscle glucocorticoid signaling in accelerating obesity and glucose intolerance via hyperinsulinemia

Hiroki Yamazaki,1 Masaaki Uehara,2 Noritada Yoshikawa,3 Akiko Kuribara-Souta,4 Motohisa Yamamoto,2 Yasuko Hirakawa,1 Yasuaki Kabe,1 Makoto Suematsu,1 and Hirotoshi Tanaka1

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Yamazaki, H. in: JCI | PubMed | Google Scholar |

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Uehara, M. in: JCI | PubMed | Google Scholar |

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Yoshikawa, N. in: JCI | PubMed | Google Scholar |

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Kuribara-Souta, A. in: JCI | PubMed | Google Scholar

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Yamamoto, M. in: JCI | PubMed | Google Scholar |

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Hirakawa, Y. in: JCI | PubMed | Google Scholar

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Kabe, Y. in: JCI | PubMed | Google Scholar

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Suematsu, M. in: JCI | PubMed | Google Scholar

1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

2Department of Rheumatology and Allergy, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3Center for Arthritis and Rheumatic Diseases, Kawasaki Municipal Hospital, Kawasaki-shi, Kanagawa, Japan

4Department of Cell Processing and Transfusion, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Find articles by Tanaka, H. in: JCI | PubMed | Google Scholar

Published March 14, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.162382.
Copyright © 2023, Yamazaki et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 14, 2023 - Version history
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Abstract

Metabolic crosstalk from skeletal muscle to multiple organs is important for maintaining homeostasis, and its dysregulation can lead to various diseases. Chronic glucocorticoid administration often induces muscle atrophy and metabolic disorders such as diabetes and central obesity; however, the detailed underlying mechanism remains unclear. We previously reported that the deletion of glucocorticoid receptor (GR) in skeletal muscle increases muscle mass and reduces fat mass through muscle–liver–fat communication under physiological conditions. In this study, we show that muscle GR signaling plays a crucial role in accelerating obesity through the induction of hyperinsulinemia. Fat accumulation in liver and adipose tissue, muscle atrophy, hyperglycemia, and hyperinsulinemia induced by chronic corticosterone (CORT) treatment improved in muscle-specific GR knockout (GRmKO) mice. Such CORT-induced fat accumulation was alleviated by suppressing insulin production (streptozotocin injection), indicating that hyperinsulinemia enhanced by muscle GR signaling promotes obesity. Strikingly, glucose intolerance and obesity in ob/ob mice without CORT treatment were also improved in GRmKO mice, indicating that muscle GR signaling contributes to obesity-related metabolic changes, regardless of systemic glucocorticoid levels. Thus, this study provides new insight for the treatment of obesity and diabetes by targeting muscle GR signaling.

Graphical Abstract
graphical abstract
Supplemental material

View SupplementaryFigures.pdf : Supplementary Figures 1-12

View SupplementaryTables.xlsx : Supplementary Tables 1-12

Version history
  • Version 1 (March 14, 2023): In-Press Preview
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