Diabetologie und Stoffwechsel 2018; 13(03): 272
DOI: 10.1055/s-0038-1657801
Freie Vorträge
Georg Thieme Verlag KG Stuttgart · New York

A miR-29a-driven negative feedback loop regulates the glucocorticoid receptor in health and disease

Authors

  • C Glantschnig

    1   Helmholtz Zentrum München, Institute for Diabetes and Cancer (IDC), Neuherberg, Germany
    2   Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg, Germany
    3   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

  • M Koenen

    4   Institute of Comparative Molecular Endocrinology, Ulm, Germany

  • M Gil Lozano

    1   Helmholtz Zentrum München, Institute for Diabetes and Cancer (IDC), Neuherberg, Germany
    2   Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg, Germany
    3   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

  • M Karbiener

    5   Medical University of Graz, Division of Phoniatrics, Speech and Swallowing, Graz, Austria

  • CL Cummins

    6   Department of Pharmaceutical Sciences, University of Toronto, Toronto, Canada

  • M Blüher

    7   Clinic for Enocrinology and Nephrology, Medical Research Center, Leipzig, Germany

  • J Tuckermann

    4   Institute of Comparative Molecular Endocrinology, Ulm, Germany

  • S Herzig

    3   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
    8   Helmholtz Zentrum München, Institute for Diabetes and Cancer (IDC), & Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany
    9   Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany

  • M Scheideler

    1   Helmholtz Zentrum München, Institute for Diabetes and Cancer (IDC), Neuherberg, Germany
    2   Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg, Germany
    3   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
Further Information

Publication History

Publication Date:
07 June 2018 (online)

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    Glucocorticoids are essential steroid hormones which control metabolic homeostasis systemically and in peripheral tissues. They are also potent anti-inflammatory agents, but in ˜30% of patients treated long-term with glucocorticoids, treatment resistance develops. Part of this is attributed to downregulation of the Glucocorticoid Receptor (GR). The molecular mechanisms involved are still unclear. Moreover, long-term glucocorticoid excess leads to metabolic disturbances and obesity, but its effects on the adipose tissue remain ambiguous.

    Here, we investigated how GR activation regulates microRNAs in both healthy adipose tissue to assess microRNA regulation during glucocorticoid excess, and in a model of rheumatoid arthritis as an example of an inflammatory disease. We found that in both states, miR-29a was induced by long-term glucocorticoid treatment, while GR protein abundance was reduced. miR-29a directly targets GR, creating a negative feedback loop which causes glucocorticoid-induced downregulation of GR. Upregulation of miR-29a depends on GR binding and dimerization, and inhibition of GR activity abolishes the induction of miR-29a. In line with these results, miR-29a inhibits adipogenesis in human preadipocytes and mediates most of its effects via GR. Finally, in human adipose tissue, miR-29a correlates inversely with GR.

    Summarized, we discovered a GR-miR-29a negative feedback loop conserved between mice and humans, in health and disease. For the first time, we elucidate a microRNA-related mechanism that might contribute to glucocorticoid resistance in peripheral tissues. Our results lay the groundwork for potential targeting of miR-29a to diminish adipose tissue side effects of long-term glucocorticoid treatment.