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An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice

Nature Medicine volume 22, pages 1120–1130 (2016)Cite this article

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Abstract

Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.

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Figure 1: Tumor cell exposure induces lipolysis, lipogenesis and energy crisis in adipocytes.
Figure 2: Diminished Ampk activity in iWAT is a key feature of various mouse models of cancer cachexia.
Figure 3: WAT loss in cancer cachexia is not mediated by Ucp1.
Figure 4: Cidea mediates disruption of Ampk integrity.
Figure 5: CIDEA expression is higher in human WAT under conditions of substantial weight loss.
Figure 6: ACIP treatment reduces WAT wasting in cachexia.

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Acknowledgements

We would like to thank K. Müller-Decker, K. Friedrich, D. Sohn, F. Ilmberger, Y. Feuchter, B. Meissburger, M. Kirilov, A. Vegiopoulos, P. Flachs, J. Hansikova, N. Petrovic and M. Christian for helpful discussions and experimental support and D.G. Hardie (University of Dundee) for Ampk-α1-specific and Ampk-α2-specific sheep antibodies. We particularly thank T. Schafmeier for comments on the manuscript. This work was supported by grants from the Swedish Cancer Fund (P.A.), the Deutsche Forschungsgemeinschaft grant He3260/8-1 (S.H.), the European Foundation for the Study of Diabetes (S.H.), the EU FP7 project DIABAT (HEALTH-F2-2011-278373; S.H.), the DKFZ–Bayer Cooperation Program (S.H.), the HGF Cross Program Topic 'Metabolic Dysfunction' (S.H.) and the HGF 'ICEMED' Program (S.H.).

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Author notes

  1. Maria Rohm and Michaela Schäfer: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany

    Maria Rohm, Michaela Schäfer, Victor Laurent, Bilgen Ekim Üstünel, Katharina Niopek, Carolyn Algire, Oksana Hautzinger, Tjeerd P Sijmonsma, Annika Zota, Dasa Medrikova, Natalia S Pellegata, Mauricio Berriel Diaz & Stephan Herzig

  2. Joint Heidelberg–IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany

    Maria Rohm, Michaela Schäfer, Victor Laurent, Bilgen Ekim Üstünel, Katharina Niopek, Carolyn Algire, Oksana Hautzinger, Tjeerd P Sijmonsma, Annika Zota, Dasa Medrikova, Natalia S Pellegata, Mauricio Berriel Diaz & Stephan Herzig

  3. Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany

    Maria Rohm, Michaela Schäfer, Victor Laurent, Bilgen Ekim Üstünel, Katharina Niopek, Annika Zota, Natalia S Pellegata, Mauricio Berriel Diaz & Stephan Herzig

  4. Department of Medicine, Lipid Laboratory, Karolinska Institute, Stockholm, Sweden

    Mikael Ryden, Agné Kulyte, Ingrid Dahlman & Peter Arner

  5. Department of Molecular Biosciences, The Wenner–Gren Institute, Stockholm University, Stockholm, Sweden

    Natasa Petrovic & Barbara Cannon

  6. Université Côte d'Azur, Nice, France

    Ez-Zoubir Amri

  7. Centre National de la Recherche Scientifique (CNRS), Nice, France

    Ez-Zoubir Amri

  8. St Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia

    Bruce E Kemp

  9. Mary MacKillop Institute for Health, Research Australian Catholic University, Melbourne, Victoria, Australia

    Bruce E Kemp

  10. Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada

    Gregory R Steinberg

  11. Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic

    Petra Janovska & Jan Kopecky

  12. Swiss Federal Institute of Technology, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland

    Christian Wolfrum

  13. Department of Medicine, University of Leipzig, Leipzig, Germany

    Matthias Blüher

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  1. Maria Rohm
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Contributions

M.Rohm, M.S., V.L., B.E.Ü., K.N., C.A., O.H., T.P.S., A.Z., D.M., N.S.P., M.Ryden, A.K., I.D., P.A., N.P., B.C., E.-Z.A., B.E.K., G.R.S., P.J., J.K., C.W., M.B. and M.B.D. performed experiments and generated experimental tools; and S.H. designed and directed the research and wrote the manuscript.

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Correspondence to Stephan Herzig.

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Rohm, M., Schäfer, M., Laurent, V. et al. An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat Med 22, 1120–1130 (2016). https://doi.org/10.1038/nm.4171

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