The Role of Hypothalamic FoxO1 on Hyperphagia in Streptozotocin-Induced Diabetic Mice

Background: Streptozotocin-induced diabetic animals are characterized by hyperphagia due to deficiencies of insulin and leptin. Forkhead box-containing protein of the O subfamily-1 (FoxO1) regulates energy homeostasis by regulating energy expenditure and food intake as well as mediating insulin and leptin signals in the hypothalamus. To identify the mediator of diabetic hyperphagia, we examined the effects of insulin or leptin on hypothalamic FoxO1 expression in a diabetic animal model. Methods: Diabetes was induced in mice (C57BL/6) by intraperitoneal administration of streptozotocin (200 mg/kg). Stainless steel cannula w as implanted into the lateral ventricle of the brain in each mouse. After three weeks, the mice were administered saline, insulin or leptin via intracerebroventricular (ICV) route. The medial hypothalamus was isolated to evaluate the mRNA expressions of FoxO1 and neuropeptides. Results: Streptozotocin-induced diabetic mice exhibited significant elevations of blood glucose and food intake and significantly low levels of serum insulin and leptin . The levels of hypothalamic FoxO1 mRNA were significantly increased in diabetic mice. The hypothalamic expression of neuropeptide Y (NPY) mRNA was increased, but the expression of preproopiomelanocortin (POMC) mRNA was decreased in diabetic mice. ICV administration of insulin or leptin attenuated the upregula tion of hypothalamic FoxO1 mRNA, and resulted in downregulation of NP Y mRNA and upregulation of POMC mRNA in diabetic mice. Conclusion: We observed that the expression of hypothalamic FoxO1 mRNA was increased in streptozotocin-induced diabetic mice, and that it was significantly attenuated by central administration of insulin or leptin. These results suggest that hypothalamic FoxO1 is the direct mediator of diabetic hyperphagia. (Korean Diabetes J 33:375-381, 2009)