Molecular medicine of adipocyte differentiation

脂肪细胞分化的分子医学

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15081203/
• 关键词: type 1 angiotensin receptor; adipose tissue remodeling; adipocytes; macrophages; fatty acids; TNFα; MKP-1; inflammation; 肥満; 脂肪組織; MCP-1; 飽和脂肪酸; TLR4; 炎症性変化; 脂肪分解; アディポサイトカイン; 遊離脂肪酸; アンジオテンシンII; 高脂肪食; 交感神経活動; アンジオテンシン受容体; type 1 angiotensin receptor; adipose tissue remodeling; adipocytes; macrophages; fatty acids; TNFα; MKP-1; inflammation; 肥満; 脂肪組織; MCP-1; 飽和脂肪酸; TLR4; 炎症性変化; 脂肪分解; アディポサイトカイン; 遊離脂肪酸; アンジオテンシンII; 高脂肪食; 交感神経活動; アンジオテンシン受容体

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）在调节体液稳态和血压控制中起重要作用。血管紧张素原（AGT）是所有的前体，主要由肝脏产生。它也发生在脂肪组织中，在肥胖症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，我们检查了高脂饮食中缺乏Agtrla（Agtrla^< - / - >小鼠）的小鼠的代谢表型。我们发现，相对于野生型同窝小鼠，饮食引起的体重增加和肥胖的衰减以及Agtrla^< - / - >小鼠的胰岛素抵抗，这表明Agtrl在代谢综合征中的作用。这些观察结果表明AGTRL在肥胖发展中的病理生理作用2。脂肪组织重塑脂肪组织的分子机制以脂肪细胞肥大为特征，其次是……在血管生成，巨噬细胞浸润和促炎性脂肪细胞因子产生中增加的ES，这表明先前未识别的动态变化在功能和形式上可能是addipose to a addipipsude tose remod tose nupe indipsude''的动态变化。使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，旁分线环涉及饱和脂肪酸和源自脂肪细胞和巨噬细胞的TNFα，分别建立了一个奇妙的循环，使肥胖脂肪组织中的炎症变化令人振奋。有趣的是，饱和脂肪酸通过巨噬细胞诱导的脂肪细胞脂肪分解从肥大的脂肪细胞大量释放，作为TLR4的自然发生的配体，从而诱导肥胖脂肪组织的炎症变化。肥胖的脂肪组织。我们最近发现，MCP-1的产生是诱导的，随后是肥胖脂肪组织在巨噬细胞浸润之前的ERK激活和MKP-1下调。对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MKP-1下调通过MKP-1下调的ERK激活与MCP-1的产生有关，这表明MKP-1的下调对肥胖脂肪细胞的炎性变化至关重要。我们的数据有助于阐明“脂肪组织重塑”的分子机制，并确定一种新型的治疗靶标，该靶标可能会减少肥胖诱导的脂肪组织注射。较少的