Feed-forward regulation between GPR120 and PPAR gamma.

GPR120 和 PPAR gamma 之间的前馈调节。

• 批准号: 10886882
• 负责人: DAYOUNG OH
• 金额: $ 13.94万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10886882
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Agonist; Antiinflammatory Effect; Automobile Driving; Biology; Blood Vessels; Cells; Collaborations; Data; Development; Diet; Dose; Doxycycline; Energy Intake; Exhibits; Fibrosis; Functional disorder; Funding; G-Protein-Coupled Receptors; Genes; Health; Heterogeneity; High Fat Diet; Homeostasis; Hyperplasia; Hypertrophy; Inflammation; Inflammatory; Knockout Mice; Laboratories; Link; Maintenance; Mediating; Metabolic; Metabolic syndrome; Molecular; Molecular Target; Mus; Nutrient; Obesity; Omega-3 Fatty Acids; PPAR gamma; Pathologic; Pericytes; Phenotype; Phosphorylation; Physiological; Production; Publishing; Rana; Regulation; Role; Signal Transduction; Testing; Tissue Expansion; Transplantation; Variant; adipokines; adult obesity; cell type; design; diet-induced obesity; feeding; improved; in vivo; insight; insulin sensitivity; lipid biosynthesis; mouse model; novel; novel therapeutics; overexpression; pharmacologic; precursor cell; progenitor; receptor; recruit; response; side effect; stem cells; tool

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.

项目概要/摘要 肥胖症中白色脂肪组织（WAT）的病理性扩张的特点是脂肪细胞肥大， 炎症和纤维化；然而，引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）因肥胖而表现出区域变异，但原因尚不清楚。 下一个资助周期，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决定肥胖中 WAT 的健康状况。 在成年小鼠的 APC 中，无论有或没有 GPR120 刺激，脂肪生成的主要调节因子都可以确定 是否通过 GPR120 刺激介导的 PPARγ 增加 APC 的成脂能力 过度表达导致肥胖中 WAT 的健康扩增，此外还检查了丢失的负面影响。 壁细胞GPR120在WAT在高脂肪饮食喂养下扩张时，我们还捕获了精确的分子 GPR120 激活如何驱动 APC 中 PPARγ 活性的调节和抑制的机制 肥胖条件下纤维炎症祖细胞（FIP）的炎症这一概念。 在上一个资助周期中表明，PPARγ 和 GPR120 激活的组合已被证明 作为附加效应以及使用低剂量的 PPARγ 激动剂、TZD 来减轻不良副作用 与 GPR120 激动剂化合物 A (CpdA) 组合因此，在本次更新申请中，我们确定了 PPARγ 和 GPR120 激活在健康 WAT 重塑中的作用取决于壁细胞 PPARγ 和 GPR120 前馈调节与 GPR120 刺激介导的抗炎作用。 强调了 APC 在药理学上改善肥胖代谢健康的潜力。