title: Mutations in cytoplasmic dynein lead to a Huntington's disease-like defect in energy metabolism of brown and white adipose tissues.
abstract: The molecular motor dynein is regulated by the huntingtin protein, and Huntington's disease (HD) mutations of huntingtin disrupt dynein motor activity. Besides abnormalities in the central nervous system, HD animal models develop prominent peripheral pathology, with defective brown tissue thermogenesis and dysfunctional white adipocytes, but whether this peripheral phenotype is recapitulated by dynein dysfunction is unknown. Here, we observed prominently increased adiposity in mice harboring the legs at odd angles (Loa/+) or the Cramping mutations (Cra/+) in the dynein heavy chain gene. In Cra/+ mice, hyperadiposity occurred in the absence of energy imbalance and was the result of impaired norepinephrine-stimulated lipolysis. A similar phenotype was observed in 3T3L1 adipocytes upon chemical inhibition of dynein showing that loss of functional dynein leads to impairment of lipolysis. Ex vivo, dynein mutant adipose tissue displayed increased reactive oxygen species production that was, at least partially, responsible for the decreased cellular responses to norepinephrine and subsequent defect in stimulated lipolysis. Dynein mutation also affected norepinephrine efficacy to elicit a thermogenic response and led to morphological abnormalities in brown adipose tissue and cold intolerance in dynein mutant mice. Interestingly, protein levels of huntingtin were decreased in dynein mutant adipose tissue. Collectively, our results provide genetic evidence that dynein plays a key role in lipid metabolism and thermogenesis through a modulation of oxidative stress elicited by norepinephrine. This peripheral phenotype of dynein mutant mice is similar to that observed in various animal models of HD, lending further support for a functional link between huntingtin and dynein.
authors.affiliation: Inserm, U692, Strasbourg, F-67085 France.
authors.forename: Judith
authors.initials: J
authors.lastname: Eschbach
authors.forename: Anissa
authors.initials: A
authors.lastname: Fergani
authors.forename: Hugues
authors.initials: H
authors.lastname: Oudart
authors.forename: Jean-Patrice
authors.initials: JP
authors.lastname: Robin
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rene
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Gonzalez de Aguilar
authors.forename: Yves
authors.initials: Y
authors.lastname: Larmet
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Majid
authors.initials: M
authors.lastname: Hafezparast
authors.forename: Birgit
authors.initials: B
authors.lastname: Schwalenstocker
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
mesh_terms: D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D056445:Cytoplasmic Dyneins / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D022722:Thermogenesis / Q000235:genetics
chemical_list: D000316:Adrenergic alpha-Agonists; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018343:Receptors, Adrenergic, beta-2; D056445:Cytoplasmic Dyneins; D009638:Norepinephrine