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

• 批准号: 10431889
• 负责人: YUXIANG SUN
• 金额: $ 31.23万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431889
• 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; antagonist; 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; translational potential

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外周组织的慢性炎症，从而导致广泛的代谢功能障碍，这种现象被称为“元炎症”。巨噬细胞是间性炎症的关键免疫调节剂，由促炎M1和抗炎M2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很大的潜力。然而，巨噬细胞极化的调控机制尚不清楚。生长激素促分泌受体（GHS-R），已知与营养敏感致肥肠道激素ghrelin结合。我们对GHS-R全缺失小鼠的研究表明，GHS-R是一种必需的代谢调节剂；它的信号激活是全身代谢和炎症状态的指示。我们报道了GHS-R消融术可以预防饮食引起的肥胖和衰老过程中的胰岛素抵抗。我们也有证据表明，GHS-R在巨噬细胞中具有细胞自主作用，并且GHS-R的敲低使巨噬细胞向M2谱转移。我们假设GHS-R是巨噬细胞极化的关键调节因子；在饮食诱导的肥胖中，GHS-R将巨噬细胞重编程为促炎状态，导致脂肪组织和肝脏的炎症和脂质积累。我们将利用新生成的骨髓特异性GHS-R敲除和再表达小鼠，揭示GHS-R在巨噬细胞极化中的作用和相关机制。将进行以下全面和互补的具体目标：目标1。确定巨噬细胞GHS-R是否促进饮食性肥胖下巨噬细胞的促炎极化，增加脂肪组织和肝脏的炎症和脂质沉积（体内研究）。目标2。研究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的炎症（离体研究）。目标3。探讨GHS-R调控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间性炎症中起关键作用。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，进而调节促炎细胞因子的表达。这一建议将为巨噬细胞表型转换的调控提供新的范式，并可能揭示一种连接营养感知、炎症和代谢的新的调控机制。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有力的策略。

项目成果

Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation.

• DOI: 10.1016/j.molmet.2023.101852
• 发表时间: 2024-01
• 期刊: MOLECULAR METABOLISM
• 影响因子: 8.1
• 作者: Kim, Da Mi;Lee, Jong Han;Pan, Quan;Han, Hye Won;Shen, Zheng;Eshghjoo, Sahar;Wu, Chia-Shan;Yang, Wanbao;Noh, Ji Yeon;Threadgill, David W.;Guo, Shaodong;Wright, Gus;Alaniz, Robert;Sun, Yuxiang
• 通讯作者: Sun, Yuxiang

Thrifty Hormone Ghrelin: The Secret of Aging Muscularly

节俭激素胃饥饿素：肌肉衰老的秘密

• DOI: 10.35248/2329-8847.20.s3.005
• 发表时间: 2020
• 期刊: Journal of aging science
• 作者: Yuxiang Sun

A Cautionary Note for COVID-19 Survivors: Potential Long-term Risk for Alzheimer's Disease.

• DOI: 10.34297/ajbsr.2020.09.001415
• 发表时间: 2020
• 期刊: American journal of biomedical science & research
• 作者: Sun Y

Age-dependent remodeling of gut microbiome and host serum metabolome in mice.

• DOI: 10.18632/aging.202525
• 发表时间: 2021-02-17
• 期刊: Aging
• 作者: Wu CS;Muthyala SDV;Klemashevich C;Ufondu AU;Menon R;Chen Z;Devaraj S;Jayaraman A;Sun Y
• 通讯作者: Sun Y

Nutrient-Sensing Ghrelin Receptor in Macrophages Modulates Bisphenol A-Induced Intestinal Inflammation in Mice.

• DOI: 10.3390/genes14071455
• 发表时间: 2023-07-16
• 期刊: GENES
• 影响因子: 3.5
• 作者: Ye, Xiangcang;Liu, Zeyu;Han, Hye Won;Noh, Ji Yeon;Shen, Zheng;Kim, Da Mi;Wang, Hongying;Guo, Huiping;Ballard, Johnathan;Golovko, Andrei;Morpurgo, Benjamin;Sun, Yuxiang
• 通讯作者: Sun, Yuxiang