title: Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62.
abstract: Signaling cascades that control adipogenesis are essential in the regulation of body weight and obesity. The adaptor p62 controls pathways that modulate cell differentiation. We report here that p62(-/-) mice develop mature-onset obesity, leptin resistance, as well as impaired glucose and insulin intolerance. The metabolic rate was significantly reduced in p62(-/-) nonobese mice, which displayed increased mRNA levels of PPAR-gamma and reduced levels of UCP-1 in adipose tissue. Basal activity of ERK was enhanced in fat from nonobese mutant mice. Embryo fibroblasts from p62(-/-) mice differentiated better than the wild-type controls into adipocytes, which was abrogated by pharmacological inhibition of the ERK pathway. p62 is induced during adipocyte differentiation and inhibits ERK activation by direct interaction. We propose that p62 normally antagonizes basal ERK activity and adipocyte differentiation and that its loss leads to the hyperactivation of ERK that favors adipogenesis and obesity.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Angelina
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Angeles
authors.initials: A
authors.lastname: Durán
authors.forename: Mohammed
authors.initials: M
authors.lastname: Selloum
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Diez-Guerra
authors.forename: Juana María
authors.initials: JM
authors.lastname: Flores
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: María T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis; D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
chemical_list: C490981:Gtf2h1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D048049:Extracellular Signal-Regulated MAP Kinases