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.

Centre National de la Recherche Scientifique Nice France

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

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

Department of Medicine University of Leipzig Leipzig Germany

Department of Molecular Biosciences The Wenner Gren Institute Stockholm University Stockholm Sweden

Deutsches Zentrum für Diabetesforschung Neuherberg Germany

Institute for Diabetes and Cancer Helmholtz Center Munich Neuherberg Germany

Joint Heidelberg IDC Translational Diabetes Program Inner Medicine 1 Heidelberg University Hospital Heidelberg Germany

Lipid Laboratory Department of Medicine Karolinska Institute Stockholm Sweden

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

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

Swiss Federal Institute of Technology Institute of Food Nutrition and Health Schwerzenbach Switzerland

Université Côte d'Azur Nice France

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