| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2005: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2003: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Research Abstract |
The present study aimed to understant the energy sensing mechanism in the brain to regulate feeding and reproduction.
Glucokinase (GK), an enzyme playing a key role in sensing blood glucose levels, is expressed in the various brain areas. The present study revealed that the transcription start sites of GK gene in the brain areas, such as the wall of the fourth ventricle (4V), hypothalamic ventromedial nucleus, lateral hypothalamus, and raphe obsculus nuclei, were located near the pancreatic-type promoter. Of the above brain areas, the wall of the 4V sowed decreased transcription of the major B1 isoform of GK after the peripheral injection of 2-deoxyglucose, a glucose inhibitor, suggesting that the brain area may sense the decreased availability of glucose at the transcriptional level.
Diabetic rats show increased food intake and severe ketosis. The present study revealed that injection of 3-hydroxybutylate (3HB), a ketone body, into the 4V hunger responses, such as increased food intake
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and decreased gonadotropin release in normal rats. Next, we hypothesized that the ependymocytes lining, the 4V sense ketone bodies, as well as glucose, to regulate reproductive functions and feeding behavior. To determine if the increased food intake is mediated by monocarboxylate transporter in the 4V in diabetic rats and if the ependymocytes lining 4V respond to 3HB in vitro, p-Chloromercuri benzese sulphonic acid (pCMBS), a monocarboxylate transporter 1 (MCT1) inhibitor, was injected into the 4V of normal or streptozotocin (STZ)-induced diabetic rats. In addition, in vitro responses of the intracellular calcium concentration ([Ca^<2+>]i) to ketone bodies was determined in dispersed ependymocytes taken from the 4V of normal rats. The results showed that increased food intake was reduced by the administration pCMBS into the 4V in a dose-dependent manner in the diabetic rats. In vitro [Ca^<2+>]i was increased by 3HB in the ependymocytes. Immunohistochemistry showed that MCT1 was located in the 4V ependymocytes. These results suggest that increased food intake is induced by the increased ketone bodies in the circulation. The ependymocytes in the hindbrain may be a ketone body sensor mediating pathological or physiological changes in the food intake. Less
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