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¥76,800,000 (Direct Cost : ¥76,800,000)
Fiscal Year 2007 : ¥14,400,000 (Direct Cost : ¥14,400,000)
Fiscal Year 2006 : ¥14,400,000 (Direct Cost : ¥14,400,000)
Fiscal Year 2005 : ¥16,000,000 (Direct Cost : ¥16,000,000)
Fiscal Year 2004 : ¥16,000,000 (Direct Cost : ¥16,000,000)
Fiscal Year 2003 : ¥16,000,000 (Direct Cost : ¥16,000,000)
We have studied the role of brown adipose tissue (BAT) thermogenesis in the regulation of energy substrate metabolism and adiposity in mice and dogs, particularly focusing on the sympathetic nerve regulation of UCP1, a key molecule of BAT thermogenesis.
1. Treatment with an agonist for β3-adrenoceptor, which is present in adipocytes, increased BAT thermogenesis, lipid mobilization and whole body energy expenditure without notable effects on food intake, finally resulting in a marked reduction of white fat weight and the size of adipocytes in wild-type (WT), but not in UCP1-knockout, mice. Similar thermogenic and anti-obesity effects were also found when mice were treated with leptin, a major endogenous anorectic signal molecule.
2. The effects of β3-adrenergic stimulation were also examined in dogs. Daily treatment of obese beagle dogs with a β3-adrenoceptor agonist resulted in a marked reduction of body fat content estimated by CT, and apparent UCP1 expression in subcutaneous adipose ti
All these results indicate a significant role of UCP1-dependent BAT thermogenesis in the anti-obesity effect of β3-adrenoceptor agonists and leptin, and in the regulation of energy balance.
3. The thermogenesis-linked glucose utilization in BAT was studied particularly focusing on the role of UCP1. Noradrenaline (NA) increased tissue AMP levels, 5'-AMP-activated protein kinase activity, and 2-deoxyglucose (2-DG) uptake into BAT in WT mice, while these stimulatory effects of NA were much attenuated in UCP1-KO mice. Thus, the sympathetically stimulated glucose utilization in BAT is due to the serial activation of UCP1 and AMP-kinase, and thereby reflects the BAT activity in vivo.
4. Glucose utilization into adipose tissue was also examined monitoring tissue fluoro-deoxyglucose uptake by positron emission tomography in healthy adult volunteers, and found to be enhanced after cold exposure and lower in obese than lean subjects. These findings, being against a well-accepted idea that BAT is absent in adult humans, suggest a significant role of BAT in energy metabolism in man, as in the mouse and dog. Less