Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4
Muramyl Dipeptide-Based Postbiotics Mitigate Obesity-Induced Insulin Resistance via IRF4
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DOI：
10.1016/j.cmet.2017.03.021
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发表时间：
2017-05-02
期刊：
影响因子：
29
通讯作者：
Schertzer, Jonathan D.
中科院分区：
文献类型：
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作者：
Cavallari, Joseph F.;Fullerton, Morgan D.;Schertzer, Jonathan D.
肠道生态失调导致肥胖和胰岛素抵抗，但抗生素、益生元或益生菌的干预可能受到微生物组成的特异性或持续变化的限制。益生菌包括细菌成分，如脂多糖，已被证明在代谢性内毒素血症期间促进胰岛素抵抗。我们发现，细菌细胞壁衍生的胞壁酰二肽（MDP）是一种需要NOD 2的胰岛素增敏后生物。注射MDP降低了肥胖小鼠的脂肪炎症和葡萄糖耐受不良，而不会导致体重减轻或改变微生物组的组成。MDP降低肥胖和低水平内毒素血症时的肝脏胰岛素抵抗。NOD 1激活的胞肽使葡萄糖耐量恶化。IRF 4区分了对不同类型肽聚糖的相反血糖反应，并且是肥胖和内毒素血症期间MDP/NOD 2诱导的胰岛素敏化和较低代谢组织炎症所需的。IRF 4通过NOD 1因葡萄糖耐受不良加重而被禁用。Mifamurtide是一种具有孤儿药地位的基于MDP的药物，在肥胖小鼠中以临床相关剂量是一种胰岛素增敏剂。
Intestinal dysbiosis contributes to obesity and insulin resistance, but intervening with antibiotics, prebiotics, or probiotics can be limited by specificity or sustained changes in microbial composition. Postbiotics include bacterial components such as lipopolysaccharides, which have been shown to promote insulin resistance during metabolic endotoxemia. We found that bacterial cell wall-derived muramyl dipeptide (MDP) is an insulin-sensitizing postbiotic that requires NOD2. Injecting MDP lowered adipose inflammation and reduced glucose intolerance in obese mice without causing weight loss or altering the composition of the microbiome. MDP reduced hepatic insulin resistance during obesity and lowlevel endotoxemia. NOD1-activating muropeptides worsened glucose tolerance. IRF4 distinguished opposing glycemic responses to different types of peptidoglycan and was required for MDP/NOD2-induced insulin sensitization and lower metabolic tissue inflammation during obesity and endotoxemia. IRF4 was dispensable for exacerbated glucose intolerance via NOD1. Mifamurtide, an MDP-based drug with orphan drug status, was an insulin sensitizer at clinically relevant doses in obese mice.