PPAR-ALPHA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在过去的一年里，我们的临床工作主要集中在人类脂肪组织中表达的脂联素受体。脂肪衍生蛋白脂联素增强了啮齿动物的胰岛素作用。它的循环水平在肥胖和2型糖尿病患者中降低，并在改善胰岛素作用的同时被噻唑烷二酮类药物增加。脂联素在转基因小鼠中的过度表达导致某些脂肪储存的异常增大(内分泌学145：367,2004)，表明脂联素对脂肪组织起直接作用。虽然最近的一份报告证实了最近发现的两种脂联素受体在许多人类组织中的表达，但没有对脂肪组织进行检查(自然423：762,2003)。 对12名接受择期腹部手术的非糖尿病患者的皮下和大网膜脂肪组织中的基因表达进行了量化。在一个亚组中，脂肪细胞和基质细胞立即用胶原酶消化分离。AdipoR1的RNA拷贝数(质粒标准曲线，归一化为GAPDH)普遍比AdipoR2高10倍，两种受体在皮下和大网膜组织中的表达相似。虽然脂联素基因仅在脂肪细胞中表达，但其受体在脂肪细胞和基质细胞中都有表达。BMI和受体表达水平之间没有关联。 为了确定噻唑烷二酮类药物对脂肪组织基因表达的影响，对8例糖尿病患者服用吡格列酮45 mg或安慰剂21天后进行脂肪组织活检。虽然吡格列酮使脂联素的表达增加了2倍，但AdipoR1和AdipoR2的变化很小。 两种脂联素受体亚型都在人类脂肪中表达，其中AdipoR1的含量要丰富得多。与脂联素不同，这些受体在脂肪细胞和间质脂肪细胞中都有表达，并且受噻唑烷二酮类化合物的影响最小。有必要进一步研究以确定这些受体在人类中的生理意义。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our clinical endeavors this past year have focused on adiponectin receptors expressed in human adipose tissue. The fat-derived protein adiponectin enhances insulin action in rodents. Its circulating levels are reduced in obesity and type 2 diabetes mellitus, and increased by thiazolidinediones in concert with improved insulin action. Adiponectin overexpression in transgenic mice caused abnormal enlargement of certain fat depots (Endocrinology 145:367, 2004), suggesting that adiponectin exerts direct effects on fat tissue. While a recent report confirmed the expression of two recently discovered adiponectin receptors in many human tissues, no fat tissues were examined (Nature 423:762, 2003). Gene expression was quantified in subcutaneous and omental adipose tissue from twelve nondiabetic patients undergoing elective abdominal surgery. In a subgroup, adipocytes and stromal cells were immediately separated by collagenase digestion. RNA copy numbers (plasmid standard curves, normalized to GAPDH) of AdipoR1 were universally 10-fold higher than AdipoR2, and expression of both receptors was similar in subcutaneous and omental tissue. While adiponectin gene expression was specific to adipocytes, the receptors were expressed in both adipocytes and stromal cells. There was no association between BMI and receptor expression levels. To determine the effects of thiazolidinediones on adipose tissue gene expression, fat was biopsied in 8 diabetic subjects after pioglitazone 45 mg or placebo for 21 days. While pioglitazone increased adiponectin expression 2-fold, changes in AdipoR1 and AdipoR2 were minimal. Both adiponectin receptor subtypes are expressed in human fat, with AdipoR1 being much more abundant. Unlike adiponectin, the receptors are expressed in both adipocytes and stromal adipose cells and are minimally affected by thiazolidinediones. Further study to determine the physiologic significance of these receptors in humans is warranted.