title: Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function.
abstract: Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K. Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain nuria.barbarroja.exts@juntadeandalucia.es sr441@medschl.cam.ac.uk ajv22@medschl.cam.ac.uk.
authors.forename: Nuria
authors.initials: N
authors.lastname: Barbarroja
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K. nuria.barbarroja.exts@juntadeandalucia.es sr441@medschl.cam.ac.uk ajv22@medschl.cam.ac.uk.
authors.forename: Sergio
authors.initials: S
authors.lastname: Rodriguez-Cuenca
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Nygren
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K. Lipids and Atherosclerosis Research Unit, Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Camargo
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K. Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Pirraco
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Joana
authors.initials: J
authors.lastname: Relat
authors.affiliation: Departamento de Farmacología, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cuadrado
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pellegrinelli
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K.
authors.forename: Gema
authors.initials: G
authors.lastname: Medina-Gomez
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba, Reina Sofia University Hospital, Córdoba, Spain.
authors.forename: Chary
authors.initials: C
authors.lastname: Lopez-Pedrera
authors.affiliation: CIBER in Physiopathology of Obesity and Nutrition (CB06/03), Instituto de Salud Carlos III, Madrid, Spain Instituto de Investigación Biomédica de Málaga/Hospital Virgen de la Victoria, Malaga, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Tinahones
authors.affiliation: College of Health, University of Utah, Salt Lake City, UT Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, UT.
authors.forename: J David
authors.initials: JD
authors.lastname: Symons
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: VTT Technical Research Centre of Finland, Espoo, Finland Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.affiliation: Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K. Wellcome Trust Sanger Institute, Hinxton, U.K. nuria.barbarroja.exts@juntadeandalucia.es sr441@medschl.cam.ac.uk ajv22@medschl.cam.ac.uk.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002518:Ceramides; D007328:Insulin; C109343:dihydroceramide; D044943:Fatty Acid Desaturases