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

项目摘要 慢性营养过剩和肥胖症诱导组织如脂肪组织中的低度炎症， 肝脏，炎症导致这些组织中的进一步代谢功能障碍。这种代谢触发的 炎症被称为“后炎症”，其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。巨噬细胞是继发性炎症的关键免疫调节剂， 由两种主要亚型组成：促炎性M1和抗炎性M2。新的证据表明 促进巨噬细胞抗炎极化具有令人兴奋的潜力，可以逆转 继发性炎症然而，巨噬细胞极化的调节机制还不清楚。 G蛋白偶联受体，生长激素促分泌素受体（GHS-R），是一种已知的营养素受体， 感觉到肠激素生长激素释放肽Ghrelin促进肥胖和胰岛素抵抗。全球GHS-R消融保护 对抗饮食诱导的肥胖和衰老中的胰岛素抵抗，显示脂肪组织炎症减少 和肝脏。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作用， GHS-R敲低降低内毒素诱导的巨噬细胞促炎性转变这个假设 GHS-R是一种关键的炎症调节因子，有助于炎症的发病机制。 肥胖和非酒精性脂肪性肝炎（NASH）; GHS-R重新编程巨噬细胞极化， 促炎状态，导致脂肪组织和肝脏中的炎症和代谢功能障碍。 为了阐明GHS-R在巨噬细胞极化中的作用和相关机制， 将使用特异性GHS-R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性极化， 增加脂肪组织和肝脏中的炎症和脂质沉积（体内研究）。2.审查是否 GHS-R细胞自主调节巨噬细胞极化，巨噬细胞中的GHS-R活化促进 炎症并通过内分泌和/或旁分泌作用增强脂肪细胞和肝细胞的脂毒性 (ex体内研究）。3.研究GHS-R介导的巨噬细胞极化的分子机制。 我们假设GHS-R代谢重编程巨噬细胞; GHS-R，通过胰岛素信号，调节巨噬细胞的功能。 控制脂肪酸氧化、葡萄糖代谢和线粒体功能的信号通路， 巨噬细胞这一建议将揭示一个新的范式调节巨噬细胞极化，并将 可能揭示了一种新的调节机制，将营养感测、炎症和代谢联系起来。这 这项提案还将提供"概念验证"证据，证明靶向巨噬细胞中的GHS-R是否是一种有效的治疗方法。 独特和强大的战略，打击肥胖和炎症。

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.