title: Inhibition of hypothalamic Foxo1 expression reduced food intake in diet-induced obesity rats.
abstract: Insulin signalling in the hypothalamus plays a role in maintaining body weight. The forkhead transcription factor Foxo1 is an important mediator of insulin signalling in the hypothalamus. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase/Akt signalling pathway, but the role of hypothalamic Foxo1 in insulin resistance and obesity remains unclear. Here, we identify that a high-fat diet impaired insulin-induced hypothalamic Foxo1 phosphorylation and degradation, increasing the nuclear Foxo1 activity and hyperphagic response in rats. Thus, we investigated the effects of the intracerebroventricular (i.c.v.) microinfusion of Foxo1-antisense oligonucleotide (Foxo1-ASO) and evaluated the food consumption and weight gain in normal and diet-induced obese (DIO) rats. Three days of Foxo1-ASO microinfusion reduced the hypothalamic Foxo1 expression by about 85%. i.c.v. infusion of Foxo1-ASO reduced the cumulative food intake (21%), body weight change (28%), epididymal fat pad weight (22%) and fasting serum insulin levels (19%) and increased the insulin sensitivity (34%) in DIO but not in control animals. Collectively, these data showed that the Foxo1-ASO treatment blocked the orexigenic effects of Foxo1 and prevented the hyperphagic response in obese rats. Thus, pharmacological manipulation of Foxo1 may be used to prevent or treat obesity.
authors.affiliation: Departamento de Clínica Médica, FCM, Universidade Estadual de Campinas, Campinas, SP, Brazil.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Ropelle
authors.forename: José R
authors.initials: JR
authors.lastname: Pauli
authors.forename: Patrícia
authors.initials: P
authors.lastname: Prada
authors.forename: Dennys E
authors.initials: DE
authors.lastname: Cintra
authors.forename: Guilherme Z
authors.initials: GZ
authors.lastname: Rocha
authors.forename: Juliana C
authors.initials: JC
authors.lastname: Moraes
authors.forename: Marisa J S
authors.initials: MJ
authors.lastname: Frederico
authors.forename: Gabrielle
authors.initials: G
authors.lastname: da Luz
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Pinho
authors.forename: José B C
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Licio A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario A
authors.initials: MA
authors.lastname: Saad
authors.forename: Cláudio T
authors.initials: CT
authors.lastname: De Souza