Rohm, M., Schafer, M., Laurent, V., Ustunel, B. E., Niopek, K., Algire, C., Hautzinger, O., Sijmonsma, T. P., Zota, A., Medrikova, D., Pellegata, N. S., Ryden, M., Kulyte, A., Dahlman, I., Arner, P., Petrovic, N., Cannon, B., Amri, E. Z., Kemp, B. E., Steinberg, G. R., Janovska, P., Kopecky, J., Wolfrum, C., Bluher, M., Berriel Diaz, M., and Herzig, S. (2016). Nat Med 22, 1120-1130. doi: 10.1038/nm.4171

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.