Inhibition of hypothalamic Foxo1 expression reduced food intake in diet-induced obesity rats.
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.
Ropelle
Eduardo R
ER
Departamento de Clínica Médica, FCM, Universidade Estadual de Campinas, Campinas, SP, Brazil.
Pauli
José R
JR
Prada
Patrícia
P
Cintra
Dennys E
DE
Rocha
Guilherme Z
GZ
Moraes
Juliana C
JC
Frederico
Marisa J S
MJ
da Luz
Gabrielle
G
Pinho
Ricardo A
RA
Carvalheira
José B C
JB
Velloso
Licio A
LA
Saad
Mario A
MA
De Souza
Cláudio T
CT