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

GHS-R 在元炎症期间巨噬细胞重编程中的作用

基本信息

批准号：
10194483
负责人：
YUXIANG SUN
金额：
$ 31.28万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10194483
关键词：
Ablation Adipocytes Adipose tissue Age Aging Anti-Inflammatory Agents Attenuated Binding Biology Bone Marrow CD14 Antigen Cell physiology Cells Chronic Coculture Techniques Cues Data Deposition Diet Endocrine Endotoxins Exhibits G-Protein-Coupled Receptors GTP-Binding Proteins Genus Hippocampus Glycolysis Goals Hepatic Hepatocyte High Fat Diet Hormones Immunomodulators Inflammation Inflammatory Insulin Resistance Knock-out Kupffer Cells Light Link Lipids Lipopolysaccharides Liver Liver Dysfunction Mass Spectrum Analysis Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Molecular Morphology Mus Myelogenous Obesity Palmitates Peripheral Phenotype Phosphoproteins Process Protein Subunits Reporting Role Saturated Fatty Acids Series Signal Pathway Signal Transduction Steatohepatitis Thinness Tissues cytokine detection of nutrient diet-induced obesity dietary extracellular fatty acid oxidation feeding gain of function ghrelin glucose uptake growth hormone secretagogue receptor in vivo insulin sensitivity insulin signaling knock-down loss of function macrophage novel obesity treatment obesogenic overexpression paracrine response transcriptome sequencing

项目摘要

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.

肥胖会促进脂肪组织和肝脏等周围组织的慢性炎症，从而导致广泛的代谢功能障碍，这种现象称为“元炎症”，巨噬细胞是元炎症的关键免疫调节剂，由促炎性 M1 组成。重编程巨噬细胞极化被认为在治疗肥胖引起的炎症和代谢功能障碍方面具有巨大潜力，但巨噬细胞极化的调节机制尚不清楚。我们对 GHS-R 整体缺失小鼠的研究表明，生长激素促分泌素受体 (GHS-R) 与营养敏感的肥胖肠道激素 ghrelin 结合，其信号激活是一种重要的代谢调节剂。我们报道了 GHS-R 消除可以预防饮食引起的肥胖和衰老过程中的胰岛素抵抗。我们发现 GHS-R 是巨噬细胞极化的关键调节因子；GHS-R 在饮食诱导的肥胖下将巨噬细胞重新编程为促炎症状态，从而导致炎症和脂质积累。我们将利用我们新产生的骨髓特异性 GHS-R 敲除和重新表达来揭示 GHS-R 在巨噬细胞极化中的作用和相关机制。将进行以下全面和补充的具体目标：目标 1. 确定巨噬细胞 GHS-R 在饮食诱导的肥胖下是否促进巨噬细胞的促炎极化，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炎症（体外研究）。 3. 研究 GHS-R 调节巨噬细胞极化的分子机制我们预计 GHS-R 在脂肪组织和肝脏的巨噬细胞极化和元炎症中起着至关重要的作用。重新编程脂肪酸氧化和糖酵解的信号通路，进而调节促炎细胞因子的表达，该提议将揭示调节巨噬细胞表型转换的新范例。可能会发现一种将营养传感、炎症和代谢联系起来的新调控机制。该提案还将提供“概念验证”证据，证明针对巨噬细胞中的 GHS-R 是否是对抗肥胖和炎症的独特而强大的策略。