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

巨噬细胞重编程和炎症衰老中的营养感应 GHS-R

• 批准号: 10436515
• 负责人: YUXIANG SUN
• 金额: $ 5.3万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436515
• 关键词: Ablation; Adipocytes; Adipose tissue; Age; Aging; Anti-Inflammatory Agents; Attenuated; Binding; Bone Marrow; Cells; Chronic; Chronic Disease; Coculture Techniques; Deposition; Diabetes Mellitus; Diet; Endocrine; Endotoxins; Exhibits; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Hepatic; Hepatocyte; High Fat Diet; Hormones; Immunomodulators; Impairment; In Vitro; Inflammaging; Inflammation; Inflammatory; Insulin Resistance; Knockout Mice; Kupffer Cells; Light; Link; Lipids; Lipopolysaccharides; Liver; Liver Dysfunction; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolic stress; Metabolism; Mitochondria; Molecular; Morphology; Muramidase; Mus; Myelogenous; Obesity; Overnutrition; Palmitates; Pathogenesis; Pathologic Processes; Pathology; Peripheral; Phenotype; Prevention; Process; Protein Subunits; Receptor Activation; Receptor Cell; Role; Signal Pathway; Signal Transduction; Steatohepatitis; Thinness; Tissues; base; cytokine; detection of nutrient; diet-induced obesity; dietary; fatty acid oxidation; ghrelin; glucose metabolism; growth hormone secretagogue receptor; in vivo; insulin sensitivity; insulin signaling; knock-down; liver inflammation; loss of function; macrophage; nonalcoholic steatohepatitis; novel; obesogenic; paracrine; receptor; response

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.

项目概要 慢性营养过剩和肥胖会引起脂肪组织等组织的轻度炎症， 肝脏，炎症会导致这些组织进一步代谢功能障碍。 炎症被称为“元炎症”，它是许多慢性疾病病理过程的基础 例如肥胖、胰岛素抵抗和糖尿病，巨噬细胞是元炎症的关键免疫调节剂。 新的证据表明，它由两种主要亚型组成：促炎性 M1 和抗炎性 M2。 促进巨噬细胞抗炎极化具有逆转病理学的令人兴奋的潜力 然而，巨噬细胞极化的调节机制尚不清楚。 G 蛋白偶联受体、生长激素促分泌素受体 (GHS-R) 是一种已知的营养受体 感知肠道激素 Ghrelin 促进肥胖和胰岛素抵抗。 对抗饮食引起的肥胖和衰老过程中的胰岛素抵抗，显示脂肪组织炎症减少 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，并且 GHS-R 敲低可减少内毒素诱导的巨噬细胞促炎性转变。 提议认为 GHS-R 是元炎症的关键调节因子，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 将巨噬细胞极化重新编程为 促炎症状态，导致脂肪组织和肝脏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，新生的骨髓- 将使用特定的 GHS-R 敲除小鼠。将使用以下全面且互补的特定目标。 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的炎症和脂质沉积（体内研究） 2. 检查是否。 GHS-R细胞自主调节巨噬细胞极化，巨噬细胞中的GHS-R激活促进 通过内分泌和/或旁分泌作用消除炎症并增强脂肪细胞和肝细胞的脂毒性 （离体研究） 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 通过胰岛素信号传导对巨噬细胞进行代谢重编程； 控制脂肪酸氧化、葡萄糖代谢和线粒体功能的信号通路 该提案将揭示调节巨噬细胞极化的新范式，并将 可能会发现一种将营养传感、炎症和代谢联系起来的新调节机制。 该提案还将提供“概念验证”证据，证明巨噬细胞中的 GHS-R 靶点是否是一种 对抗肥胖和炎症的独特而强大的策略。