|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1999 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1998 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1997 : ¥1,900,000 (Direct Cost : ¥1,900,000)
The βィイD23ィエD2-adrenergic receptor (βィイD23ィエD2-AR) plays a significant role in the control of lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT) of rodents and humans. In 1995, a Trp to Arg (Trp64Arg) substitution of human βィイD23ィエD2-AR was discovered in Pima Indians. We found that the allelic frequency of this variant reaches 19-20% in Japanese, and this mutation was associated with visceral fat obesity, insulin resistance syndrome, a resistance to weight loss, and diabetic complications. In developed nations, lifestyle-related diseases are increasing year by year. It is a most important point for such countries to prevent obesity in order to decrease lifestyle-related diseases. However, there are many uncertainties regarding the mechanism of how genetic factors induces obesity. Therefore, in this study, we have investigated the mechanism by which the mutation of βィイD23ィエD2-AR induces obesity, using 3T3L1 cells transfected permanently with the Trp64Arg mutation or the wild-type, and, furthermore, using human omental adipocytes with and without the Trp64Arg mutation. We found that the absolute amounts of accumulated cAMP were lower in the cells transfected with the Trp64Arg mutation than with the wild type, and, the Trp64Arg mutation deteriorated lipolysis induced by βィイD23ィエD2-AR agonist in human omental adipocytes. These findings suggest that the Trp64Arg mutation could result in lower activation of hormone-sensitive lipoprotein lipase and hence lipolysis. Furthermore, we performed a phase 1 study using AJ-9677 (selective βィイD23ィエD2-AR agonist for human), and found that this agent per os could significantly increase plasma free fatty acid and glycerol levels in dose-dependent manners without side effects in humans. Therefore, we expect to perform a phase 2 study of this agent with obese and diabetic patients.