Molecular medicine of adipocyte differentiation

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)在体液平衡调节和血压控制中起着重要作用。血管紧张素原(AGT)是ALL的前体，主要由肝脏产生。它也出现在脂肪组织中，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Agtrla的小鼠(Agtrla^&lt；-/-&gt；小鼠)在高脂饮食中的代谢表型。我们发现，与野生型小鼠相比，Agtrla^&lt；-/-&gt；小鼠的饮食诱导的体重增加和肥胖以及胰岛素抵抗都得到了缓解，这表明Agtrl在代谢综合征中发挥了作用。这些观察结果提示Agtrl在肥胖发生中的病理生理学作用。脂肪组织重塑的分子机制肥胖脂肪组织的特点是脂肪细胞肥大，然后是…增加更多的ES参与血管生成、巨噬细胞浸润和促炎脂肪细胞因子的产生，提示了以前未知的功能和形态的动态变化，这可能被称为脂肪组织重塑。利用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，分别由脂肪细胞和巨噬细胞来源的饱和脂肪酸和肿瘤坏死因子α组成的旁分泌循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，通过巨噬细胞诱导脂肪细胞的脂肪分解，肥大的脂肪细胞大量释放饱和脂肪酸，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，在巨噬细胞向肥胖脂肪组织的渗透中发挥作用。我们最近发现，肥胖脂肪组织中MCP-1的产生被诱导，随后ERK被激活，MKP-1被下调，然后巨噬细胞浸润。体外对3T3-LL脂肪细胞的研究表明，通过下调MKP-1激活ERK参与了脂肪细胞肥大过程中MCP-1产生的增加，提示MKP-1下调在肥胖早期肥大脂肪细胞的炎性变化中起关键作用。我们的数据有助于阐明脂肪组织重塑的分子机制，并确定可能减少肥胖引起的脂肪组织炎症的新的治疗靶点。较少

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