NOD1 activators link innate immunity to insulin resistance.
NOD1 activators link innate immunity to insulin resistance.
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作者：
Schertzer JD;Tamrakar AK;Magalhães JG;Pereira S;Bilan PJ;Fullerton MD;Liu Z;Steinberg GR;Giacca A;Philpott DJ;Klip A
胰岛素抵抗与慢性炎症有关，免疫系统的参与因素正在出现。我们假设作用于先天免疫系统的不同细胞内模式识别受体的细菌元件，例如作用于核苷酸寡聚结构域（NOD）蛋白的细菌肽聚糖（PGN），导致胰岛素抵抗。对喂食高脂肪饮食 (HFD) 16 周的野生型 (WT) 和 NOD1/2−/− 双敲除小鼠的代谢和炎症特性进行了评估。通过注射含有内消旋二氨基庚二酸的 PGN 或最小生物活性 PGN 基序的模拟物（分别激活 NOD1 和 NOD2）的小鼠，通过高胰岛素正常血糖钳测量胰岛素抵抗。使用酶联免疫吸附测定对注射 NOD 配体的小鼠进行全身和组织特异性炎症评估。在体外暴露于 NOD 配体的脂肪细胞和原代肝细胞中评估细胞因子分泌、葡萄糖摄取和胰岛素信号传导。 NOD1/2−/− 小鼠免受 HFD 诱导的炎症、脂质积累和外周胰岛素不耐受的影响。相反，NOD1蛋白的直接激活会导致胰岛素抵抗。 NOD1 配体在 WT 小鼠中 6 小时内诱导外周和肝脏胰岛素抵抗，但 NOD1−/− 小鼠则不然。 NOD2 配体仅适度减少外周葡萄糖的处理。 NOD1 配体引起循环促炎介质的微小变化，但引起脂肪组织炎症以及肌肉 AS160 和肝脏 FOXO1 的胰岛素抵抗。离体后，NOD1 配体引起促炎细胞因子分泌，并直接损害脂肪细胞中胰岛素刺激的葡萄糖摄取。 NOD1 配体还直接在 WT 小鼠的原代肝细胞中引起炎症和胰岛素抵抗，但 NOD1−/− 小鼠则不会。我们将 NOD 蛋白确定为先天免疫成分，与饮食引起的炎症和胰岛素不耐受有关。细菌 PGN 模拟物对 NOD 蛋白的急性激活会导致全身胰岛素抵抗，这支持了对独特细菌线索的先天免疫反应直接导致胰岛素抵抗的概念。因此，NOD1 可能是先天免疫和新陈代谢之间的新联系。
Insulin resistance associates with chronic inflammation, and participatory elements of the immune system are emerging. We hypothesized that bacterial elements acting on distinct intracellular pattern recognition receptors of the innate immune system, such as bacterial peptidoglycan (PGN) acting on nucleotide oligomerization domain (NOD) proteins, contribute to insulin resistance. Metabolic and inflammatory properties were assessed in wild-type (WT) and NOD1/2−/− double knockout mice fed a high-fat diet (HFD) for 16 weeks. Insulin resistance was measured by hyperinsulinemic euglycemic clamps in mice injected with mimetics of meso-diaminopimelic acid–containing PGN or the minimal bioactive PGN motif, which activate NOD1 and NOD2, respectively. Systemic and tissue-specific inflammation was assessed using enzyme-linked immunosorbent assays in NOD ligand–injected mice. Cytokine secretion, glucose uptake, and insulin signaling were assessed in adipocytes and primary hepatocytes exposed to NOD ligands in vitro. NOD1/2−/− mice were protected from HFD-induced inflammation, lipid accumulation, and peripheral insulin intolerance. Conversely, direct activation of NOD1 protein caused insulin resistance. NOD1 ligands induced peripheral and hepatic insulin resistance within 6 h in WT, but not NOD1−/−, mice. NOD2 ligands only modestly reduced peripheral glucose disposal. NOD1 ligand elicited minor changes in circulating proinflammatory mediators, yet caused adipose tissue inflammation and insulin resistance of muscle AS160 and liver FOXO1. Ex vivo, NOD1 ligand caused proinflammatory cytokine secretion and impaired insulin-stimulated glucose uptake directly in adipocytes. NOD1 ligand also caused inflammation and insulin resistance directly in primary hepatocytes from WT, but not NOD1−/−, mice. We identify NOD proteins as innate immune components that are involved in diet-induced inflammation and insulin intolerance. Acute activation of NOD proteins by mimetics of bacterial PGNs causes whole-body insulin resistance, bolstering the concept that innate immune responses to distinctive bacterial cues directly lead to insulin resistance. Hence, NOD1 is a plausible, new link between innate immunity and metabolism.
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