Molecular medicine of adipocyte differentiation

脂肪细胞分化的分子医学

基本信息

批准号：
15081203
负责人：
OGAWA Yoshihiro
金额：
$ 24.83万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2007
项目状态：
已结题

项目摘要

1. Pathophysiologic role of type 1 angiotensin receptorThe 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 remodelingObese adipose tissue is characterized by adipocyte hypertrophy, followed by increas … More 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

1。1型血管紧张素受体的病理生理作用在体液停滞和血压控制的调节中起重要作用在肥胖的发育过程中，它在体内的肥胖组织中进行了上调。。肥胖的发展。2。从脂肪细胞和巨噬细胞中，建立了一种恶性循环，其炎症会改变肥胖的脂肪组织，饱和脂肪酸，这些脂肪酸大量从肥厚的脂肪细胞年龄诱导的脂肪细胞脂肪分解中大量释放，可作为既然发生的forr4在肥胖症的过程中增加了。在肥胖的脂肪组织中起作用，在肥胖的脂肪组织中起作用。通过MKP-1下调激活在脂肪细胞肥大的过程中增加了产量1脂肪组织炎症。