title: Defective regulation of the ubiquitin/proteasome system in the hypothalamus of obese male mice.
abstract: In both human and experimental obesity, inflammatory damage to the hypothalamus plays an important role in the loss of the coordinated control of food intake and energy expenditure. Upon prolonged maintenance of increased body mass, the brain changes the defended set point of adiposity, and returning to normal weight becomes extremely difficult. Here we show that in prolonged but not in short-term obesity, the ubiquitin/proteasome system in the hypothalamus fails to maintain an adequate rate of protein recycling, leading to the accumulation of ubiquitinated proteins. This is accompanied by an increased colocalization of ubiquitin and p62 in the arcuate nucleus and reduced expression of autophagy markers in the hypothalamus. Genetic protection from obesity is accompanied by the normal regulation of the ubiquitin/proteasome system in the hypothalamus, whereas the inhibition of proteasome or p62 results in the acceleration of body mass gain in mice exposed for a short period to a high-fat diet. Thus, the defective regulation of the ubiquitin/proteasome system in the hypothalamus may be an important mechanism involved in the progression and autoperpetuation of obesity.
authors.affiliation: Laboratory of Cell Signaling (L.M.I.-S., B.B., L.B.P., M.A.P., D.S.R., A.C., S.C.V., R.F.d.M., L.F.N., A.P.A., M.M., L.A.V.), Faculty of Applied Sciences (M.A.P., M.M.), and Department of Pharmacology (G.F.A.), University of Campinas, 13084-970 Campinas, Brazil.
authors.forename: Leticia M
authors.initials: LM
authors.lastname: Ignacio-Souza
authors.forename: Bruna
authors.initials: B
authors.lastname: Bombassaro
authors.forename: Livia B
authors.initials: LB
authors.lastname: Pascoal
authors.forename: Mariana A
authors.initials: MA
authors.lastname: Portovedo
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Razolli
authors.forename: Andressa
authors.initials: A
authors.lastname: Coope
authors.forename: Sheila C
authors.initials: SC
authors.lastname: Victorio
authors.forename: Rodrigo F
authors.initials: RF
authors.lastname: de Moura
authors.forename: Lucas F
authors.initials: LF
authors.lastname: Nascimento
authors.forename: Ana P
authors.initials: AP
authors.lastname: Arruda
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Anhe
authors.forename: Marciane
authors.initials: M
authors.lastname: Milanski
authors.forename: Licio A
authors.initials: LA
authors.lastname: Velloso
mesh_terms: D000818:Animals; D001343:Autophagy; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D015430:Weight Gain; D015431:Weight Loss
chemical_list: C490981:Gtf2h1 protein, mouse; D014157:Transcription Factors; D025801:Ubiquitin; D051758:Transcription Factor TFIIH; D046988:Proteasome Endopeptidase Complex