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

0466490 - FGÚ 2017 RIV US eng J - Journal Article
Rohm, M. - Schäfer, M. - Laurent, V. - Üstünel, 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. - Janovská, Petra - Kopecký, Jan - Wolfrun, Ch. - Blüher, M. - Diaz, M. B. - Herzig, S.
An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.
Nature Medicine. Roč. 22, č. 10 (2016), s. 1120-1130. ISSN 1078-8956. E-ISSN 1546-170X
R&D Projects: GA MŠMT(CZ) 7E12073
Institutional support: RVO:67985823
Keywords : cachexia * cancer * white adipose tissue * AMPK
Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition
Impact factor: 29.886, year: 2016

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.
Permanent Link: http://hdl.handle.net/11104/0264775