Abstract

The rising incidence of obesity and related disorders such as diabetes and heart disease has focused considerable attention on the discovery of new therapeutics. One promising approach has been to increase the number or activity of brown-like adipocytes in white adipose depots, as this has been shown to prevent diet-induced obesity and reduce the incidence and severity of type 2 diabetes. Thus, the conversion of fat-storing cells into metabolically active thermogenic cells has become an appealing therapeutic strategy to combat obesity. Here, we report a screening platform for the identification of small molecules capable of promoting a white-to-brown metabolic conversion in human adipocytes. We identified two inhibitors of Janus kinase (JAK) activity with no precedent in adipose tissue biology that stably confer brown-like metabolic activity to white adipocytes. Importantly, these metabolically converted adipocytes exhibit elevated UCP1 expression and increased mitochondrial activity. We further found that repression of interferon signalling and activation of hedgehog signalling in JAK-inactivated adipocytes contributes to the metabolic conversion observed in these cells. Our findings highlight a previously unknown role for the JAK–STAT pathway in the control of adipocyte function and establish a platform to identify compounds for the treatment of obesity.

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Acknowledgements

The authors thank I. Clausen, M. Kapps, R. Schmucki and A. Schuler for technical support, K. Christensen and M. Graf for stem cell support, L. Badi for preliminary data analysis, C. Solier, A. Schell-Steven and T. Bergauer for experimental planning and M. Pawlak (Natural and Medical Sciences Institute at the University of Tübingen) for RPPA analyses. A.M. was supported by the Roche Postdoctoral Fellowship (RPF) program (2011–2013). This research was supported in part by F. Hoffmann-La Roche; grant R01DK095384 (C.A.C. and Y.K.L.) and R01DK097768 (C.A.C.) from the United States Institutes of Health (NIH); and Harvard University.

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Affiliations

  1. Roche Pharma Research and Early Development, Roche Innovation Center Basel, 124 Grenzacherstrasse, Basel CH 4070, Switzerland

    • Annie Moisan
    • , Jitao David Zhang
    • , Claas A. Meyer
    • , Michael Prummer
    • , Sannah Zoffmann
    • , Hoa Hue Truong
    • , Martin Ebeling
    • , Anna Kiialainen
    • , Régine Gérard
    •  & Kurt E. Amrein
  2. Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Massachusetts 02138, USA

    • Youn-Kyoung Lee
    • , Carolyn S. Hudak
    • , Fang Xia
    • , Robert T. Schinzel
    •  & Chad A. Cowan
  3. Center for Regenerative Medicine, Massachusetts General Hospital, Boston Massachusetts 02114, USA

    • Youn-Kyoung Lee
    • , Carolyn S. Hudak
    • , Fang Xia
    • , Robert T. Schinzel
    •  & Chad A. Cowan

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Contributions

A.M. designed and performed experiments, analysed data and wrote the manuscript; Y-K.L. performed experiments, analysed data and edited the manuscript; R.G., C.S.H. and F.X. performed experiments; J.D.Z. and M.E. performed bioinformatics analyses and contributed to the main text related to Fig. 7; H.H.T., S.Z. and M.P. performed high-content imaging analysis; A.K. performed RNA-seq; C.A.M. and R.T.S. supervised stem cell activities; K.E.A. supervised the project and C.A.C. supervised the project and wrote the manuscript. A.M., Y-K.L., R.G., C.S.H., M.P., J.D.Z., H.H.T., S.Z. and A.K. contributed to description of Methods.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Annie Moisan or Chad A. Cowan.

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DOI

https://doi.org/10.1038/ncb3075

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