Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
Am J Physiol Endocrinol Metab. 2020 Apr 1;318(4):E579-E585. doi: 10.1152/ajpendo.00033.2020. Epub 2020 Feb 26.
Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose-lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in nonhematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that were evident during a glucose tolerance test (GTT) in high-fat diet (HFD)-fed wild-type (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in nonhematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance but NOD2 activation in nonhematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.
定义宿主受体和细菌成分的代谢后果可以帮助解释微生物组如何影响代谢疾病。激活核苷酸结合寡聚化结构域包含 (NOD)1 的细菌肽聚糖会恶化葡萄糖控制，而 NOD2 激活则改善血糖。受体相互作用丝氨酸/苏氨酸蛋白激酶 2 (RIPK2) 是 NOD1 和 NOD2 引发先天免疫所必需的。RIPK2 在 NOD1 与 NOD2 对血糖的不同影响中的作用尚不清楚。我们发现，在小鼠急性低水平内毒素挑战期间，全身敲除 RIPK2 可消除 NOD1 或 NOD2 激活对血糖的所有影响。已知造血细胞中的 NOD1 参与肥胖小鼠的胰岛素抵抗和代谢性炎症。尚不清楚造血细胞中的 RIPK2 是否需要 NOD2 激活的降血糖和抗炎作用。我们假设非造血细胞中的 RIPK2 决定了 NOD2 激活的血糖效应。我们发现，全身敲除 RIPK2 可防止在高脂肪饮食 (HFD) 喂养的野生型 (WT) 小鼠中葡萄糖耐量试验 (GTT) 期间明显的重复 NOD2 激活的降血糖作用。NOD2 激活可降低 GTT 期间的血糖，并降低造血细胞中 RIPK2 缺失小鼠的脂肪组织炎症。我们得出结论，非造血细胞中的 RIPK2 介导 NOD2 激活后生元的降血糖和抗炎作用。我们提出了一个模型，其中内毒素和 NOD1 配体在造血细胞中协同作用以促进胰岛素抵抗，但非造血细胞中的 NOD2 激活促进 RIPK2 依赖性免疫耐受和降低炎症和胰岛素抵抗。
