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
Departamento de Clínica Médica, FCM, Universidade Estadual de Campinas, Campinas, SP, Brazil.
J Physiol. 2009 May 15;587(Pt 10):2341-51. doi: 10.1113/jphysiol.2009.170050. Epub 2009 Mar 30.
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.
下丘脑的胰岛素信号传导在维持体重方面发挥作用。叉头转录因子Foxo1是下丘脑胰岛素信号传导的重要介质。Foxo1通过磷脂酰肌醇-3-激酶/蛋白激酶B信号通路刺激促食欲神经肽Y和刺鼠相关蛋白的转录，但下丘脑Foxo1在胰岛素抵抗和肥胖中的作用仍不清楚。在此，我们发现高脂饮食会损害胰岛素诱导的下丘脑Foxo1磷酸化和降解，增加大鼠的核Foxo1活性和摄食亢进反应。因此，我们研究了脑室内微量注射Foxo1反义寡核苷酸（Foxo1-ASO）的效果，并评估了正常和饮食诱导肥胖（DIO）大鼠的食物摄入量和体重增加情况。连续三天微量注射Foxo1-ASO可使下丘脑Foxo1表达降低约85%。脑室内注射Foxo1-ASO可降低DIO大鼠的累积食物摄入量（21%）、体重变化（28%）、附睾脂肪垫重量（22%）和空腹血清胰岛素水平（19%），并增加胰岛素敏感性（34%），但对对照动物无此作用。总体而言,这些数据表明,Foxo1-ASO治疗可阻断Foxo1的促食欲作用,并预防肥胖大鼠的摄食亢进反应。因此,Foxo1的药物调控可用于预防或治疗肥胖。
