title: An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.
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: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Maria
authors: M
authors: Rohm
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Michaela
authors: M
authors: Schäfer
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Victor
authors: V
authors: Laurent
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Bilgen Ekim
authors: BE
authors: Üstünel
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Katharina
authors: K
authors: Niopek
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.
authors: Carolyn
authors: C
authors: Algire
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.
authors: Oksana
authors: O
authors: Hautzinger
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.
authors: Tjeerd P
authors: TP
authors: Sijmonsma
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Annika
authors: A
authors: Zota
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.
authors: Dasa
authors: D
authors: Medrikova
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Natalia S
authors: NS
authors: Pellegata
authors: Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Mikael
authors: M
authors: Ryden
authors: Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Agné
authors: A
authors: Kulyte
authors: Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Ingrid
authors: I
authors: Dahlman
authors: Lipid Laboratory, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors: Peter
authors: P
authors: Arner
authors: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors: Natasa
authors: N
authors: Petrovic
authors: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors: Barbara
authors: B
authors: Cannon
authors: Université Côte d'Azur, Nice, France.|Centre National de la Recherche Scientifique (CNRS), Nice, France.
authors: Ez-Zoubir
authors: 0000-0001-8426-5396
authors: EZ
authors: Amri
authors: St Vincent's Institute of Medical Research, University of Melbourne, Fitzroy, Victoria, Australia.|Mary MacKillop Institute for Health, Research Australian Catholic University, Melbourne, Victoria, Australia.
authors: Bruce E
authors: BE
authors: Kemp
authors: Department of Medicine, Division of Endocrinology and Metabolism, McMaster University, Hamilton, Ontario, Canada.
authors: Gregory R
authors: GR
authors: Steinberg
authors: Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors: Petra
authors: P
authors: Janovska
authors: Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors: Jan
authors: J
authors: Kopecky
authors: Swiss Federal Institute of Technology, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland.
authors: Christian
authors: C
authors: Wolfrum
authors: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors: Matthias
authors: M
authors: Blüher
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Mauricio
authors: M
authors: Berriel Diaz
authors: Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.|Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine 1, Heidelberg University Hospital, Heidelberg, Germany.|Deutsches Zentrum für Diabetesforschung, Neuherberg, Germany.
authors: Stephan
authors: S
authors: Herzig
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism* / Q000494:pharmacology; D052438:Adipocytes, White / Q000187:drug effects* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects* / Q000378:metabolism; D002100:Cachexia / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects*; D050155:Lipogenesis / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000150:complications / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D022722:Thermogenesis / Q000187:drug effects; D000071256:Uncoupling Protein 1 / Q000187:drug effects / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C112510:Cidea protein, mouse; D010446:Peptide Fragments; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C554549:Prkab1 protein, mouse; D055372:AMP-Activated Protein Kinases