Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation.
Nutrient-sensing growth hormone secretagogue receptor in macrophage programming and meta-inflammation.
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DOI：
10.1016/j.molmet.2023.101852
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发表时间：
2024-01
影响因子：
8.1
通讯作者：
Sun, Yuxiang
中科院分区：
文献类型：
--
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
肥胖相关的慢性炎症，又称元炎症，是肥胖相关合并症的关键致病因素。生长激素促分泌受体（GHSR）介导营养敏感激素ghrelin在食物摄入和脂肪沉积中的作用。我们之前报道过全球Ghsr消融可以预防饮食引起的炎症和胰岛素抵抗，但其作用部位和机制尚不清楚。巨噬细胞是meta炎症的关键驱动因素。为了揭示GHSR在巨噬细胞中的作用，我们制造了骨髓特异性GHSR敲除小鼠（LysM-Cre;Ghsrf/f）。LysM-Cre;对Ghsrf/f小鼠和对照Ghsrf/f小鼠进行5个月的高脂饮食（HFD）诱导肥胖。在体内，进行了食物摄入、身体活动和能量消耗的代谢分析，以及葡萄糖和胰岛素耐量试验（GTT和ITT）。终止时，用流式细胞术和组织学方法分析腹腔巨噬细胞（pm）、附睾白色脂肪组织（eWAT）和肝脏。在离体研究中，从小鼠中产生骨髓源性巨噬细胞（bmmdms），并用棕榈酸（PA）或脂多糖（LPS）处理。在体外研究中，研究了Ghsr过表达或胰岛素受体底物2 （Irs2）敲低的巨噬细胞RAW264.7细胞。我们发现，高热量饲喂下，饲料中Ghsr的表达增加。在体内，hfd喂养LysM-Cre；Ghsrf/f小鼠在不影响食物摄入量或体重的情况下表现出明显减轻的全身炎症和胰岛素抵抗。组织分析显示，饲喂hfd的LysM-Cre；Ghsrf/f小鼠单核/巨噬细胞浸润、促炎激活和脂质积累显著减少，eWAT和肝脏中脂质相关巨噬细胞（lam）升高。在体外，ghsr缺陷巨噬细胞对PA或lps诱导的促炎极化具有保护作用，表现为糖酵解减少，脂肪酸氧化增加，NF-κ b核易位减少。在分子水平上，GHSR通过PKA-CREB-IRS2-AKT2信号通路代谢调控巨噬细胞极化。这些新结果表明巨噬细胞GHSR在meta炎症的发病机制中起关键作用，巨噬细胞GHSR促进巨噬细胞浸润，诱导促炎极化。这些令人兴奋的发现表明，GHSR可能作为治疗肥胖及其相关合并症的新的免疫治疗靶点。GHSR是间性炎症的关键调节因子。巨噬细胞GHSR通过调节巨噬细胞的浸润和极化来控制肥胖患者的免疫稳态和胰岛素敏感性。1. 在体内，骨髓特异性Ghsr缺乏可减少全身炎症和胰岛素抵抗。2. 在eWAT和肝脏中，骨髓特异性Ghsr缺乏减少巨噬细胞浸润和促炎巨噬细胞极化，从而减少组织炎症、脂肪肥大和肝脏脂质积累。3. 机制上，GHSR通过调节PKA-CREB-IRS2-AKT2通路促进m1 -巨噬细胞极化。巨噬细胞GHSR通过调节巨噬细胞编程控制肥胖后的元炎症。在体内，髓细胞特异性Ghsr缺乏症（Ghsr- m - φ ko）可减轻饮食诱导的全身炎症和胰岛素抵抗。在eWAT和肝脏中，ghsr - m - φ ko减少饮食诱导的巨噬细胞浸润和脂质沉积，显示lam升高。在巨噬细胞中，GHSR重塑M1极化，重编程代谢途径，并刺激NF-κB核易位。机制上，GHSR通过调节PKA-CREB-IRS2-AKT2通路促进m1 -巨噬细胞极化。
Obesity-associated chronic inflammation, aka meta-inflammation, is a key pathogenic driver for obesity-associated comorbidity. Growth hormone secretagogue receptor (GHSR) is known to mediate the effects of nutrient-sensing hormone ghrelin in food intake and fat deposition. We previously reported that global Ghsr ablation protects against diet-induced inflammation and insulin resistance, but the site(s) of action and mechanism are unknown. Macrophages are key drivers of meta-inflammation. To unravel the role of GHSR in macrophages, we generated myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsrf/f). LysM-Cre;Ghsrf/f and control Ghsrf/f mice were subjected to 5 months of high-fat diet (HFD) feeding to induce obesity. In vivo, metabolic profiling of food intake, physical activity, and energy expenditure, as well as glucose and insulin tolerance tests (GTT and ITT) were performed. At termination, peritoneal macrophages (PMs), epididymal white adipose tissue (eWAT), and liver were analyzed by flow cytometry and histology. For ex vivo studies, bone marrow-derived macrophages (BMDMs) were generated from the mice and treated with palmitic acid (PA) or lipopolysaccharide (LPS). For in vitro studies, macrophage RAW264.7 cells with Ghsr overexpression or Insulin receptor substrate 2 (Irs2) knockdown were studied. We found that Ghsr expression in PMs was increased under HFD feeding. In vivo, HFD-fed LysM-Cre;Ghsrf/f mice exhibited significantly attenuated systemic inflammation and insulin resistance without affecting food intake or body weight. Tissue analysis showed that HFD-fed LysM-Cre;Ghsrf/f mice have significantly decreased monocyte/macrophage infiltration, pro-inflammatory activation, and lipid accumulation, showing elevated lipid-associated macrophages (LAMs) in eWAT and liver. Ex vivo, Ghsr-deficient macrophages protected against PA- or LPS-induced pro-inflammatory polarization, showing reduced glycolysis, increased fatty acid oxidation, and decreased NF-κB nuclear translocation. At molecular level, GHSR metabolically programs macrophage polarization through PKA-CREB-IRS2-AKT2 signaling pathway. These novel results demonstrate that macrophage GHSR plays a key role in the pathogenesis of meta-inflammation, and macrophage GHSR promotes macrophage infiltration and induces pro-inflammatory polarization. These exciting findings suggest that GHSR may serve as a novel immunotherapeutic target for the treatment of obesity and its associated comorbidity. GHSR is a critical regulator of meta-inflammation. Macrophage GHSR controls immune homeostasis and insulin sensitivity under obesity by regulating macrophage infiltration and polarization. 1. In vivo, myeloid-specific Ghsr deficiency reduces systemic inflammation and insulin resistance. 2. In eWAT and liver, myeloid-specific Ghsr deficiency decreases macrophage infiltration and pro-inflammatory macrophage polarization, thus reducing tissue inflammation, adipose hypertrophy, and hepatic lipid accumulation. 3. Mechanistically, GHSR promotes M1-macrophage polarization by modulating PKA-CREB-IRS2-AKT2 pathway. Macrophage GHSR controls meta-inflammation under obesity by regulating macrophage programming. In vivo, myeloid-specific Ghsr deficiency (Ghsr-MφKO) attenuates diet-induced systemic inflammation and insulin resistance. In eWAT and liver, Ghsr-MφKO reduces diet-induced macrophage infiltration and lipid deposition, showing elevated LAMs. In macrophages, GHSR remodels M1 polarization, reprograms metabolic pathways, and stimulates NF-κB nuclear translocation. Mechanistically, GHSR promotes M1-macrophage polarization by modulating PKA-CREB-IRS2-AKT2 pathway.
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影响因子：
3.7
作者：
Demers A;Caron V;Rodrigue-Way A;Wahli W;Ong H;Tremblay A
通讯作者：
Tremblay A
DOI：
10.1073/pnas.0910177106
发表时间：
2009-10-27
影响因子：
11.1
作者：
Adelman, Karen;Kennedy, Megan A.;Rogatsky, Inez
通讯作者：
Rogatsky, Inez
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
7.7
作者：
Boden, G;She, PX;Ruderman, N
通讯作者：
Ruderman, N
影响因子：
2.9
作者：
CHOMCZYNSKI, P;SACCHI, N
通讯作者：
SACCHI, N