Korean Diabetes J.  2009 Oct;33(5):375-381. 10.4093/kdj.2009.33.5.375.

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

• Nam-Goong
• Kim JG
• Kim SJ
• Hur SJ
• Lee JW
• Kim ES
• Yun CH
• Lee BJ
• Kim YI

• KMID: 2231144
• DOI: http://doi.org/10.4093/kdj.2009.33.5.375

Abstract

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 was 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 upregulation of hypothalamic FoxO1 mRNA, and resulted in downregulation of NPY 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.

Keyword

Diabetes Mellitus; Forkhead Transcription Factors; Hyperphagia; Hypothalamus; Insulin; Leptin

MeSH Terms

Animals
Blood Glucose
Brain
Catheters
Diabetes Mellitus
Down-Regulation
Eating
Energy Metabolism
Forkhead Transcription Factors
Homeostasis
Hyperphagia
Hypothalamus
Hypothalamus, Middle
Insulin
Lateral Ventricles
Leptin
Mice
Negotiating
Neuropeptide Y
Pro-Opiomelanocortin
RNA, Messenger
Stainless Steel
Streptozocin
Up-Regulation
Blood Glucose
Forkhead Transcription Factors
Insulin
Leptin
Neuropeptide Y
Pro-Opiomelanocortin
RNA, Messenger
Stainless Steel
Streptozocin

Figure

• 

  Fig. 1 Results of hypothalamic gene expression in streptozotocin induced diabetic mice. Levels of FoxO1, NPY and POMC gene expression in the hypothalamus of diabetic mice as determined by real time PCR. A, B, C. Expression levels of FoxO1, NPY and POMC mRNA were examined by real time PCR. Results are presented as means ± S.D. n = 5 per group. *P < 0.05, †P < 0.01 and ‡P < 0.001 vs. control mice.

• 

  Fig. 2 Effect of food deprivation on the mRNA level of hypothalamic FoxO1 and serum level of insulin and leptin. A, B, C. Expression levels of hypothalamic FoxO1, NPY and POMC mRNA in the animals of food deprivation for two days and in the animals of normally fed. D, E. Serum levels of insulin and leptin. Data are shown as means ± S.D. n = 5 per group; *P < 0.05, †P < 0.01 vs. control mice.

• 

  Fig. 3 Effect of i.c.v. administration of saline, insulin or leptin on hypothalamic FoxO1 expression in the streptozotocin induced diabetic mice. A, B, C. Expression levels of hypothalamic FoxO1, NPY, POMC mRNA in diabetic mice after i.c.v. administration of saline, insulin or leptin. Data are shown as the means ± S.D. n = 5 per group. *P < 0.05 and †P < 0.01 vs. control mice. ‡P < 0.05 and §P < 0.01 vs. diabetic mice.

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