Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging

项目摘要 慢性营养过剩和肥胖导致脂肪组织和 肝脏，炎症导致这些组织进一步的代谢功能障碍。这是新陈代谢引发的 炎症被称为“化炎症”，它是许多慢性疾病的病理过程的基础。 比如肥胖、胰岛素抵抗和糖尿病。巨噬细胞是化炎症的关键免疫调节剂， 包括两个主要亚型：促炎性M1和抗炎性M2。新出现的证据表明 促进巨噬细胞抗炎极化具有逆转血管病变的潜在作用 化生炎症。然而，巨噬细胞极化的调节机制还不是很清楚。 G蛋白偶联受体，生长激素促分泌素受体(GHS-R)，是一种已知的营养因子受体。 感应胃肠激素Ghrelin。Ghrelin促进肥胖和胰岛素抵抗。全球GHS-R消融保护 抗饮食引起的肥胖和衰老中的胰岛素抵抗，显示脂肪组织的炎症减少 还有肝脏。基于细胞的研究进一步表明，GHS-R在巨噬细胞中具有细胞自主效应，并且 GHS-R基因敲除可减少内毒素诱导的巨噬细胞促炎转移。这件事的假设 有观点认为，GHS-R是一种关键的化炎症调节因子，参与了 肥胖与非酒精性脂肪性肝炎(NASH)；GHS-R将巨噬细胞极化重新编程为 促炎状态，导致脂肪组织和肝脏的炎症和代谢功能障碍。 为了揭示GHS-R在巨噬细胞极化中的作用和相关机制，新生成的髓系细胞- 将使用特定的GHS-R基因敲除小鼠。以下全面和互补的具体目标将 进行：1.确定GHS-R是否促进巨噬细胞的促炎极化，以及 增加脂肪组织和肝脏中的炎症和脂肪沉积(体内研究)。2.检查是否 GHS-R细胞自主调节巨噬细胞极化，巨噬细胞中GHS-R的激活促进 通过内分泌和/或旁分泌作用增强脂肪细胞和肝细胞的炎症和脂毒性 (体外研究)。3.探讨GHS-R介导巨噬细胞极化的分子机制。 我们假设GHS-R通过代谢对巨噬细胞重新编程；GHS-R通过胰岛素信号调节 调控脂肪酸氧化、葡萄糖代谢和线粒体功能的信号通路 巨噬细胞。这一提议将阐明调节巨噬细胞极化的新范式，并将 可能会发现一种新的调节机制，将营养感知、炎症和新陈代谢联系起来。这 该提案还将为在巨噬细胞中靶向GHS-R是否将是一种 对抗肥胖和炎症的独特和强大的战略。

Project Summary Chronic over-nutrition and obesity induce low-grade inflammation in tissues such as adipose tissue and liver, the inflammation leads to further metabolic dysfunctions in these tissues. This metabolically-triggered inflammation is termed "meta-inflammation", which underlies pathological processes of many chronic diseases such obesity, insulin resistance, and diabetes. Macrophages are key immune-modulators of meta-inflammation, comprised of two main subtypes: pro-inflammatory M1 and anti-inflammatory M2. Emerging evidences suggest that promoting macrophage anti-inflammatory polarization has exciting potential for reversing the pathology of meta-inflammation. However, the regulatory mechanisms of macrophage polarization are not well understood. G-protein-coupled receptor, growth hormone secretagogue receptor (GHS-R), is a known receptor for nutrient- sensing gut hormone ghrelin. Ghrelin promotes obesity and insulin resistance. Global GHS-R ablation protects against diet-induced obesity and insulin resistance in aging, showing reduced inflammation in adipose tissue and liver. Cell-based studies further suggest that GHS-R has cell-autonomous effects in macrophages, and GHS-R knockdown decreases endotoxin-induced macrophage pro-inflammatory shift. The hypothesize of this proposal is that GHS-R is a key regulator of meta-inflammation, contributing to the pathogenesis of obesity and nonalcoholic steatohepatitis (NASH); GHS-R reprograms macrophage polarization toward a pro-inflammatory state, leading to inflammation and metabolic dysfunctions in adipose tissue and liver. To unravel the roles and pertinent mechanisms of GHS-R in macrophage polarization, newly-generated myeloid- specific GHS-R knockout mice will be used. The following comprehensive and complementary Specific Aims will be conducted: 1. Determine whether GHS-R promotes pro-inflammatory polarization of macrophages, and increases inflammation and lipid deposition in adipose tissue and liver (in vivo studies). 2. Examine whether GHS-R cell-autonomously regulates macrophage polarization, and GHS-R activation in macrophages promotes inflammation and enhances lipotoxicity in adipocytes and hepatocytes via endocrine and/or paracrine actions (ex vivo studies). 3. Investigate molecular mechanisms involved in GHS-R mediated macrophage polarization. We postulate that GHS-R metabolically reprograms macrophages; GHS-R, via insulin signaling, modulates signaling pathways to govern fatty acid oxidation, glucose metabolism, and mitochondrial function of macrophages. This proposal will shed light on a new paradigm for regulating macrophage polarization, and will likely uncover a novel regulatory mechanism linking nutrient sensing, inflammation and metabolism. This proposal will also provide “proof-of-concept” evidence for whether targeting GHS-R in macrophages would be a unique and powerful strategy for combating obesity and inflammation.