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

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, Mikael Ryden, Agné Kulyte, Ingrid Dahlman, Peter Arner, Natasa Petrovic, Barbara Cannon, Ez-Zoubir Amri, Bruce E Kemp, Gregory R Steinberg, Petra Janovska, Jan Kopecky, Christian Wolfrum, Matthias Blüher, Mauricio Berriel Diaz & Stephan Herzig 
Nature Medicine doi:10.1038/nm.4171



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.