|Budget Amount *help
¥38,800,000 (Direct Cost: ¥38,800,000)
Fiscal Year 2007: ¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 2006: ¥7,400,000 (Direct Cost: ¥7,400,000)
Fiscal Year 2005: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2004: ¥8,000,000 (Direct Cost: ¥8,000,000)
Fiscal Year 2003: ¥8,000,000 (Direct Cost: ¥8,000,000)
1. Pathophysiologic role of type 1 angiotensin receptor
The renin-angiotensin system (RAS) plays an important role in the regulation of body fluid homeostasis and blood pressure control. Angiotensinogen (Agt), the precursor of All, is produced primarily by the liver. It also occurs in the adipose tissue, where it is up-regulated during the development of obesity. To understand the functional role of Agtrl in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtrla (Agtrla^<-/-> mice) during a high-fat diet. We have found the attenuation of diet-induced body weight gain and adiposity, and insulin resistance in Agtrla^<-/-> mice relative to wild-type littermates, suggesting the role of Agtrl in the metabolic syndrome. These observations suggest the pathophysiologic role of Agtrl in the development of obesity.
2. Molecular mechanism of adipose tissue remodeling
Obese adipose tissue is characterized by adipocyte hypertrophy, followed by increas
es in angiogenesis, macrophage infiltration, and pro-inflammatory adipocytokine production, suggesting the previously unrecognized dynamic changes in function and morphology, which may be referred to as "adipose tissue remodeling". Using an in vitro co-culture composed of adipocytes and macrophages, we have provided evidence that a paracrine loop involving saturated fatty acids and TNFα derived from adipocytes and macrophages, respectively, establishes a vicious cycle that aggravates inflammatory changes in obese adipose tissue. Interestingly, saturated fatty acids, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in obese adipose tissue.
MCP-1, an important chemokine whose expression is increased during the course of obesity, plays a role in macrophage infiltration into obese adipose tissue. We have recently found that MCP-1 production is induced, which is followed by ERK activation and MKP-1 down-regulation in obese adipose tissue prior to macrophage infiltration. In vitro studies with 3T3-Ll adipocytes have demonstrated that ERK activation through MKP-1 down-regulation is involved in increased production of MCP-1 during the course of adipocyte hypertrophy, suggesting that MKP-1 down-regulation is critical for the inflammatory changes in hypertrophied adipocytes at the early stage of obesity. Our data help elucidate the molecular mechanism underlying "adipose tissue remodeling" and identify a novel therapeutic target that may reduce obesity-induced adipose tissue inflammation. Less