The role of GHS-R in macrophage reprogramming during meta-inflammation

肥胖会促进脂肪组织和肝脏等外周组织的慢性炎症，导致广泛的代谢功能障碍，这种现象被称为“元炎症”。巨噬细胞是炎症反应的关键免疫调节剂，由促炎性M1和抗炎性M2组成。重编程巨噬细胞极化被认为具有治疗肥胖诱导的炎症和代谢功能障碍的巨大潜力。然而，巨噬细胞极化的调节机制还不清楚。生长激素促分泌素受体（GHS-R），是已知的结合到营养感应肥胖的肠道激素生长素释放肽。我们对GHS-R整体缺失小鼠的研究表明，GHS-R是一种重要的代谢调节剂;其信号传导激活指示全身代谢和炎症状态。我们报道了GHS-R消融可防止饮食诱导的肥胖和衰老中的胰岛素抵抗。我们也有证据表明GHS-R在巨噬细胞中具有细胞自主性作用，GHS-R的敲低使巨噬细胞向M2谱移动。我们假设GHS-R是巨噬细胞极化的关键调节剂; GHS-R在饮食诱导的肥胖下将巨噬细胞重编程为促炎状态，导致脂肪组织和肝脏中的炎症和脂质积聚。我们将使用我们新产生的骨髓特异性GHS-R敲除和再表达小鼠来阐明GHS-R在巨噬细胞极化中的作用和相关机制。将实现以下全面和互补的具体目标：目标1。确定巨噬细胞GHS-R是否在饮食诱导的肥胖下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）。目标2.检查GHS-R是否通过细胞自主作用控制巨噬细胞极化，并通过旁分泌作用促进脂肪细胞和肝细胞中的炎症（离体研究）。目标3.研究GHS-R调节巨噬细胞极化的分子机制。我们预期GHS-R在脂肪组织和肝脏中的巨噬细胞极化和继发性炎症中具有关键作用。具体来说，我们预测GHS-R，通过胰岛素信号，重编程脂肪酸氧化和糖酵解的信号通路，反过来调节促炎细胞因子的表达。这一建议将揭示一个新的模式，调节巨噬细胞表型开关，并可能揭示一个新的调节机制，连接营养传感，炎症和代谢。该提案还将提供“概念验证”证据，证明靶向巨噬细胞中的GHS-R是否是对抗肥胖和炎症的独特而强大的策略。

Obesity promotes chronic inflammation in peripheral tissues such as adipose tissue and liver, which leads to a wide range of metabolic dysfunctions, a phenomenon called “meta-inflammation”. Macrophages are key immune-modulators of meta-inflammation, comprised of pro-inflammatory M1 and anti-inflammatory M2. Reprograming macrophage polarization is thought to have great potential for treatment of obesity-induced inflammation and metabolic dysfunctions. However, the regulatory mechanisms of macrophage polarization are not well understood. Growth hormone secretagogue receptor (GHS-R), is known to bind to nutrient-sensing obesogenic gut hormone ghrelin. Our studies with GHS-R global deletion mice have shown that GHS-R is an essential metabolic regulator; its signaling activation is indicative of systemic metabolic and inflammatory state. We reported that GHS-R ablation protects against diet-induced obesity and insulin resistance in aging. We also have evidence that GHS-R has cell-autonomous effect in macrophages, and knockdown of GHS-R shifts macrophages toward M2 spectrum. We hypothesize that GHS-R is a key regulator of macrophage polarization; GHS-R reprograms macrophages toward pro-inflammatory state under diet-induced obesity, leading to inflammation and lipid accumulation in adipose tissue and liver. We will unravel the roles and pertinent mechanisms of GHS-R in macrophage polarization using our newly-generated myeloid-specific GHS-R knockout and re-expression mice. The following comprehensive and complementary Specific Aims will be conducted: Aim 1. Determine whether macrophage GHS-R promotes pro-inflammatory polarization of macrophages under diet-induced obesity, increasing inflammation and lipid deposition in adipose tissue and liver (In vivo studies). Aim 2. Examine whether GHS-R controls macrophage polarization via cell-autonomous action, and promotes inflammation in adipocytes and hepatocytes via paracrine action (Ex vivo studies). Aim 3. Investigate molecular mechanisms by which GHS-R regulates macrophage polarization. We anticipate that GHS-R has a crucial role in macrophage polarization and meta-inflammation in adipose tissues and liver. Specifically, we predict that GHS-R, via insulin signaling, reprograms signaling pathways of fatty acid oxidation and glycolysis, in turn regulating the expression of pro-inflammatory cytokines. This proposal will shed light on a new paradigm for regulating macrophage phenotypic switch, and likely uncover a novel regulatory mechanism linking nutrient sensing, inflammation and metabolism. This proposal will also provide “proof-of-concept” evidence whether targeting GHS-R in macrophages would be an unique and powerful strategy for combating obesity and inflammation.