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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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.).
The authors declare no competing financial interests.
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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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