Feed-forward regulation between GPR120 and PPAR gamma.

项目总结/摘要 肥胖症中白色脂肪组织（WAT）的病理性扩张的特征在于脂肪细胞肥大， 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（APCs）表现出区域性的变化，对肥胖的反应，原因尚不清楚。在 下一个资金周期，我们将专注于健康的脂肪生成，并测试假设，即潜在的 从PDGFRβ+ APC募集新的脂肪细胞决定肥胖症的WAT健康。我们控制了过氧化物酶体增殖物激活受体γ的水平， 在有或没有GPR 120刺激的情况下，在成年小鼠的APC中， 是否通过GPR 120刺激介导的PPARγ增加APC的成脂能力 过表达导致肥胖症中健康的WAT扩增。除了审查损失的负面影响外， 壁细胞GPR 120在高脂饮食喂养后WAT扩增中的表达，我们还假设了精确的分子机制。 GPR 120激活如何驱动APC中PPARγ活性的调节和抑制 肥胖条件下纤维炎性祖细胞（FIPs）中的炎症。这个概念，我们 在上一个资助周期中，已经显示了PPARγ和GPR 120激活的组合， 作为累加效应，以及使用低得多的剂量的PPARγ激动剂，TZD来减轻不必要的副作用 与GPR 120激动剂化合物A（CpdA）组合。因此，在此更新申请中，我们确定 在健康WAT重塑中，PPARγ和GPR 120活化的作用依赖于壁细胞PPARγ， GPR 120前馈调节与GPR 120刺激介导的抗炎作用。我们的研究 突出了APC靶向治疗改善肥胖症代谢健康的潜力。

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.