Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62.
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.
Rodriguez
Angelina
A
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Durán
Angeles
A
Selloum
Mohammed
M
Champy
Marie-France
MF
Diez-Guerra
Francisco J
FJ
Flores
Juana María
JM
Serrano
Manuel
M
Auwerx
Johan
J
Diaz-Meco
María T
MT
Moscat
Jorge
J
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*
C490981:Gtf2h1 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D048049:Extracellular Signal-Regulated MAP Kinases