title: A switch from white to brown fat increases energy expenditure in cancer-associated cachexia.
abstract: Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Michele
authors.initials: M
authors.lastname: Petruzzelli
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Schreiber
authors.affiliation: Spectroscopy and Nuclear Magnetic Resonance Unit, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Campos-Olivas
authors.affiliation: Children's Cancer Institute Australia for Medical Research, UNSW Lowy Cancer Research Centre Building, C25 Kensington Campus UNSW, Sydney, NSW 2052, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Tsoli
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Allen
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Swarbrick
authors.affiliation: Institute of Biochemistry, Christian-Albrechts University, Olshausenstr. 40, 24118 Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Division of Immunobiology, Department of Medicine, University of Vermont, 89 Beaumont Avenue / D305 Given Building, Burlington, VT 05405, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Rincon
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Robertson
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50, 8010 Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: BBVA Foundation-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029 Madrid, Spain. Electronic address: ewagner@cnio.es.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D002001:Adipose Tissue, Brown / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D052436:Adipose Tissue, White / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002100:Cachexia / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels / Q000032:analysis; D051379:Mice; D024101:Mitochondrial Proteins / Q000032:analysis; D009369:Neoplasms / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000071256:Uncoupling Protein 1
chemical_list: D000893:Anti-Inflammatory Agents; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1