title: Double Myod and Igf2 inactivation promotes brown adipose tissue development by increasing Prdm16 expression.
abstract: Brown fat or brown adipose tissue (BAT), found in newborn mammals as small depots localized in the interscapular region, plays a prominent role in regulating thermogenesis perinatally. The physiological importance of functional BAT has been recently reasserted in human adults. Because myoblasts and adipoblasts emerge from a common mesodermal precursor, we investigated developmental determination and the reciprocal relationship between muscle and adipocyte commitment. Here we show that a mutant mouse defective for both Igf2 and Myod genes exhibits massive BAT hypertrophy compared with wild-type and single-mutant newborns. The increased adipocyte proliferation in BAT of double-mutant newborns was associated with overexpression of the brown fat-specific marker Ucp1. More strikingly, expression of the master key gene Prdm16 involved in the switch between myogenic and brown adipogenic lineages was drastically enhanced. We further demonstrate that concomitant Myod and Igf2 inactivation accelerates differentiation of a brown preadipocyte cell line and induces lipid accumulation and increased Ucp1 and Prdm16 expression. This in vitro approach brings additional support for the implication of both Myod and Igf2 in BAT development. These results provide the first in vivo evidence that a myogenic regulator together with a growth factor act simultaneously but through independent pathways to repress Prdm16, which opens potential therapeutic perspectives for human metabolic disorders.
authors.affiliation: Genetics and Development Department, Institut National de Santé et de Recherche Médicale (INSERM) U567, Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche 8104, University of Paris Descartes, Institut Cochin, Paris, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Borensztein
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.forename: Didier
authors.initials: D
authors.lastname: Montarras
authors.forename: Laurent
authors.initials: L
authors.lastname: Journot
authors.forename: Nadine
authors.initials: N
authors.lastname: Binart
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.forename: Luisa
authors.initials: L
authors.lastname: Dandolo
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: D004268:DNA-Binding Proteins; C513121:IGF2 protein, mouse; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C521133:Prdm16 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D007335:Insulin-Like Growth Factor II