1. Evidence for an important role of CIDEA in human cancer cachexia
- Author
-
Britta M Stenson, Elisabet Arvidsson Nordström, Jurga Laurencikiene, Peter Arner, Johan Permert, Thorhallur Agustsson, Mikael Rydén, Dominique Langin, Bengt Isaksson, Simon, Marie Francoise, Departments of Medicine, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Departments of Surgery, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
- Subjects
Male ,Cancer Research ,Cachexia ,White adipose tissue ,Body Mass Index ,chemistry.chemical_compound ,Mice ,Adipocyte ,Neoplasms ,Adipocytes ,MESH: Neoplasms ,MESH: Animals ,Phosphorylation ,PRDM16 ,MESH: Aged ,MESH: Middle Aged ,Fatty Acids ,MESH: Energy Metabolism ,Middle Aged ,Pyruvate dehydrogenase complex ,MESH: Fatty Acids ,MESH: Glucose ,Oncology ,MESH: Adipose Tissue, White ,Female ,Adult ,medicine.medical_specialty ,Pyruvate dehydrogenase kinase ,Adipose Tissue, White ,PDK4 ,Pyruvate Dehydrogenase Complex ,Biology ,Protein Serine-Threonine Kinases ,MESH: Protein-Serine-Threonine Kinases ,MESH: Body Mass Index ,MESH: Pyruvate Dehydrogenase Complex ,Internal medicine ,3T3-L1 Cells ,medicine ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Lipolysis ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,RNA, Messenger ,MESH: Mice ,MESH: Adipocytes ,Aged ,MESH: RNA, Messenger ,MESH: Humans ,MESH: Phosphorylation ,MESH: Apoptosis Regulatory Proteins ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,MESH: Adult ,medicine.disease ,MESH: 3T3-L1 Cells ,MESH: Male ,Endocrinology ,Glucose ,chemistry ,MESH: Cachexia ,Apoptosis Regulatory Proteins ,Energy Metabolism ,MESH: Female - Abstract
Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death–inducing DNA fragmentation factor-α–like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P < 0.05) and correlated with elevated levels of FAs and reported weight loss (P < 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P < 0.01), decreased glucose oxidation by 40% (P < 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P < 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P < 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs. [Cancer Res 2008;68(22):9247–54]
- Published
- 2008