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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肾素-血管紧张素系统（RAS）在调节体液稳态和控制血压中起重要作用。血管紧张素原（Agt）是All的前体，主要由肝脏产生。它也发生在脂肪组织中，在肥胖的发展过程中，它被上调。为了了解Agtrl在体内脂肪组织生长和代谢中的功能作用，我们研究了缺乏Agtrl的小鼠（Agtrla^<-/->小鼠）在高脂肪饮食中的代谢表型。我们发现Agtrla^<-/->小鼠与野生型小鼠相比，饮食诱导的体重增加和肥胖以及胰岛素抵抗有所减弱，这表明Agtrl在代谢综合征中的作用。这些观察结果提示Agtrl在肥胖发生中的病理生理作用。脂肪组织重塑的分子机制脂肪组织的特征是脂肪细胞肥大，随后血管生成、巨噬细胞浸润和促炎脂肪细胞因子的产生增加，提示了以前未被认识到的功能和形态的动态变化，可称为“脂肪组织重塑”。利用由脂肪细胞和巨噬细胞组成的体外共培养，我们提供了证据，表明分别来自脂肪细胞和巨噬细胞的饱和脂肪酸和TNFα的旁分泌环建立了一个恶性循环，加剧了肥胖脂肪组织的炎症变化。有趣的是，饱和脂肪酸通过巨噬细胞诱导的脂肪细胞脂解从肥大的脂肪细胞中大量释放，作为TLR4的天然配体，从而诱导肥胖脂肪组织的炎症变化。MCP-1是一种重要的趋化因子，在肥胖过程中表达增加，在巨噬细胞浸润到肥胖脂肪组织中起作用。我们最近发现，在巨噬细胞浸润之前，肥胖脂肪组织诱导MCP-1的产生，随后是ERK激活和MKP-1下调。3T3-Ll脂肪细胞的体外研究表明，在脂肪细胞肥大过程中，通过下调MKP-1激活ERK参与了MCP-1产生的增加，提示MKP-1下调对肥胖早期肥大脂肪细胞的炎症变化至关重要。我们的数据有助于阐明“脂肪组织重塑”的分子机制，并确定一种新的治疗靶点，可以减少肥胖诱导的脂肪组织炎症。少