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

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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.

authors

  • Rohm, Maria
  • Schäfer, Michaela
  • Laurent, Victor
  • Üstünel, Bilgen Ekim
  • Niopek, Katharina
  • Algire, Carolyn
  • Hautzinger, Oksana
  • Sijmonsma, Tjeerd P
  • Zota, Annika
  • Medrikova, Dasa
  • Pellegata, Natalia S
  • Ryden, Mikael
  • Kulyte, Agné
  • Dahlman, Ingrid
  • Arner, Peter
  • Petrovic, Natasa
  • Cannon, Barbara
  • Amri, Ez-Zoubir
  • Kemp, Bruce E
  • Steinberg, Gregory
  • Janovska, Petra
  • Kopecky, Jan
  • Wolfrum, Christian
  • Blüher, Matthias
  • Berriel Diaz, Mauricio
  • Herzig, Stephan

publication date

  • October 2016