Feed-forward regulation between GPR120 and PPAR gamma.

项目摘要/摘要 肥胖症中白色脂肪组织的病理性扩张以脂肪细胞肥大为特征， 炎症和纤维化；然而，触发这种适应不良重塑的因素在很大程度上是未知的。 此外，脂肪前体细胞(APC)在肥胖的反应中表现出区域性的变化，原因不明。在……里面 在下一个资金周期，我们将重点关注健康的脂肪生成，并测试以下假设： 从PDGFRβ+APC中招募新的脂肪细胞确定肥胖患者的健康状况。我们操纵PPARγ的水平， 有或无GPR120刺激的成年小鼠APC中脂肪生成的主调控因子 GPR120刺激介导的PPARγ是否增加APC的成脂能力 过度表达会导致肥胖症患者WAT的健康扩张。除了检查损失的负面影响外， 壁细胞GPR120在Wat扩增高脂饲料喂养下，我们还推测了精确的分子 GPR120激活调控APC中PPARγ活性及其抑制机制的研究 肥胖条件下纤维炎祖细胞(FIP)的炎症反应。这个概念，我们 在上一个资金周期中建议，已经显示了PPARγ和GPR120激活的组合 作为相加效应以及使用剂量低得多的PPARγ激动剂，TZDS可以减轻有害的副作用 与GPR120激动剂联合使用，化合物A(CpdA)。因此，在此续期申请中，我们确定 PPARγ和GPR120激活在健康水样重塑中的作用依赖于壁细胞PPARγ和 GPR120前馈调节与GPR120刺激介导的抗炎作用。我们的研究 强调APC作为药物靶点的潜力，以改善肥胖患者的代谢健康。

PROJECT SUMMARY/ABSTRACT Pathologic expansion of white adipose tissue (WAT) in obesity is characterized by adipocyte hypertrophy, inflammation, and fibrosis; however, factors triggering this maladaptive remodeling are largely unknown. Moreover, adipose precursor cells (APCs) exhibit reginal variation in response to obesity, for unclear reason. In the next funding cycle, we will focus on the healthy adipogenesis and test the hypothesis that the potential to recruit new adipocytes from PDGFRβ+ APCs determine WAT health in obesity. We manipulate levels of PPARγ, the master regulator of adipogenesis with or without GPR120 stimulation, in APCs of adult mice to determine whether increasing the adipogenic capacity of APCs through GPR120 stimulation-mediated PPARγ overexpression results in healthy WAT expansion in obesity. In addition to examine the negative effect of loss of mural cell GPR120 in WAT expansion upon high-fat diet feeding, we also hypothesize the precise molecular mechanism that how GPR120 activation drives modulation of PPARγ activity in APCs and inhibition of inflammation in fibro-inflammatory progenitor cells (FIPs) under obese condition. The concept, which we suggested in the previous funding cycle, that the combination of PPARγ and GPR120 activation has been shown as additive effects as well as using much lower doses of PPARγ agonist, TZDs to mitigate unwanted side effects in combination with GPR120 agonist, compound A (CpdA). Thus, in this renewal application, we determine the effect of the PPARγ and GPR120 activation in healthy WAT remodeling is dependent on mural cell PPARγ and GPR120 feed-forward regulation with GPR120 stimulation-mediated anti-inflammatory effects. Our studies highlight the potential for APCs to be targeted pharmacologically to improve metabolic health in obesity.