title: Fenretinide prevents lipid-induced insulin resistance by blocking ceramide biosynthesis.
abstract: Fenretinide is a synthetic retinoid that is being tested in clinical trials for the treatment of breast cancer and insulin resistance, but its mechanism of action has been elusive. Recent in vitro data indicate that fenretinide inhibits dihydroceramide desaturase, an enzyme involved in the biosynthesis of lipotoxic ceramides that antagonize insulin action. Because of this finding, we assessed whether fenretinide could improve insulin sensitivity and glucose homeostasis in vitro and in vivo by controlling ceramide production. The effect of fenretinide on insulin action and the cellular lipidome was assessed in a number of lipid-challenged models including cultured myotubes and isolated muscles strips incubated with exogenous fatty acids and mice fed a high-fat diet. Insulin action was evaluated in the various models by measuring glucose uptake or disposal and the activation of Akt/PKB, a serine/threonine kinase that is obligate for insulin-stimulated anabolism. The effects of fenretinide on cellular lipid levels were assessed by LC-MS/MS. Fenretinide negated lipid-induced insulin resistance in each of the model systems assayed. Simultaneously, the drug depleted cells of ceramide, while promoting the accumulation of the precursor dihydroceramide, a substrate for the reaction catalyzed by Des1. These data suggest that fenretinide improves insulin sensitivity, at least in part, by inhibiting Des1 and suggest that therapeutics targeting this enzyme may be a viable therapeutic means for normalizing glucose homeostasis in the overweight and diabetic.
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah 84602; Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore 169857. Electronic address: benjamin_bikman@byu.edu.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore 169857.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Biochemistry and, National University of Singapore, Singapore 119077; Life Sciences Institute, National University of Singapore, Singapore 119077.
authors.forename: Guanghou
authors.initials: G
authors.lastname: Shui
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore 169857.
authors.forename: M Mobin
authors.initials: MM
authors.lastname: Siddique
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75390.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: National University of Singapore High School of Mathematics and Science, Singapore 129957.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Research Unit on BioActive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut d'Investigacions Químiques i Ambientals de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), 08034 Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
authors.affiliation: Department of Biochemistry and, National University of Singapore, Singapore 119077; Life Sciences Institute, National University of Singapore, Singapore 119077; Department of Biological Sciences, National University of Singapore, Singapore 169857.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore 169857; Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002460:Cell Line; D002518:Ceramides / Q000096:biosynthesis*; D017313:Fenretinide / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D002518:Ceramides; D009097:Multienzyme Complexes; D017313:Fenretinide; C489141:Degs2 protein, mouse; D010088:Oxidoreductases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose