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Inhibition of hypothalamic Foxo1 expression reduced food intake in diet‐induced obesity rats
Author(s) -
Ropelle Eduardo R.,
Pauli José R.,
Prada Patrícia,
Cintra Dennys E.,
Rocha Guilherme Z.,
Moraes Juliana C.,
Frederico Marisa J. S.,
da Luz Gabrielle,
Pinho Ricardo A.,
Carvalheira José B. C.,
Velloso Licio A.,
Saad Mario A.,
De Souza Cláudio T.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.170050
Subject(s) - foxo1 , endocrinology , medicine , orexigenic , hypothalamus , insulin , insulin resistance , protein kinase b , obesity , insulin receptor , chemistry , biology , phosphorylation , neuropeptide y receptor , receptor , neuropeptide , microbiology and biotechnology
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.