Maternal consumption of a high-fat diet modulates the inflammatory response in their offspring, mediated by the M1 muscarinic receptor.
Maternal consumption of a high-fat diet modulates the inflammatory response in their offspring, mediated by the M1 muscarinic receptor.
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DOI：
10.3389/fimmu.2023.1273556
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发表时间：
2023
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
高脂饮食（HFD）消费与各种代谢紊乱和疾病有关。怀孕前和母亲肥胖都可能对后代的健康产生长期影响。此外，在成年期食用HFD会显著增加肥胖和代谢紊乱的风险。然而，一个有趣的现象称为肥胖悖论表明，肥胖可能会对脓毒症的死亡率结果产生保护作用。在脓毒症中，胆碱能抗炎通路（CAP）的激活可以帮助减轻全身炎症。我们采用代谢规划模型来探讨母体HFD摄入量与后代对脓毒症反应之间的关系。我们在孕前、怀孕和哺乳期给雌性小鼠喂食标准饮食（SC）或HFD。随后，我们评估了28日龄的雄性后代。 值得注意的是，我们发现HFD喂养的母鼠（HFD-0）的后代比SC喂养的母鼠（SC-0）的后代具有更高的存活率。重要的是，抑制下丘脑中参与CAP的m1毒蕈碱乙酰胆碱受体（m1 mAChR）消除了这种保护作用。不同日龄HFD-O大鼠下丘脑m1 mAChR表达均高于对照组，28日龄表达最高。用m1 mAChR激动剂治疗可以调节外周组织中的炎症反应。具体地，CAP激活在激动剂处理后HFD-0的肝脏中更大。有趣的是，与SC-0相反，脂多糖（LPS）攻击未能在HFD-0中诱导更多的炎症状态，并且激动剂处理没有额外的效果。脾免疫细胞的分析揭示了HFD-0的独特表型，其特征在于CD 4+淋巴细胞而不是CD 8+淋巴细胞水平升高。此外，基础IL 17信使RNA（mRNA）水平较低，而IL 22 mRNA水平较高，在HFD-O，我们观察到相同的模式后，LPS的挑战。 对从骨髓分离并允许分化的髓样细胞的进一步检查显示HFD-0巨噬细胞显示抗炎表型。此外，m1 mAChR激动剂治疗有助于降低两组的炎症标志物水平。总之，我们的研究结果表明，HFD-O对LPS诱导的脓毒症有保护作用，这种保护作用是由中枢m1 mAChR介导的。此外，肝脏、脾脏和骨髓分化的巨噬细胞中的炎症反应减弱。然而，更广泛的分析是必要的，以阐明具体的机制，m1 mAChR调节脓毒症期间的免疫反应。
High-fat diet (HFD) consumption is associated with various metabolic disorders and diseases. Both pre-pregnancy and maternal obesity can have long-term consequences on offspring health. Furthermore, consuming an HFD in adulthood significantly increases the risk of obesity and metabolic disorders. However, an intriguing phenomenon known as the obesity paradox suggests that obesity may confer a protective effect on mortality outcomes in sepsis. In sepsis, activation of the cholinergic anti-inflammatory pathway (CAP) can help mitigate systemic inflammation. We employed a metabolic programming model to explore the relationship between maternal HFD consumption and offspring response to sepsis. We fed female mice either a standard diet (SC) or an HFD during the pre-pregnancy, pregnancy, and lactation periods. Subsequently, we evaluated 28-day-old male offspring. Notably, we discovered that offspring from HFD-fed dams (HFD-O) exhibited a higher survival rate compared with offspring from SC-fed dams (SC-O). Importantly, inhibition of the m1 muscarinic acetylcholine receptor (m1mAChR), involved in the CAP, in the hypothalamus abolished this protection. The expression of m1mAChR in the hypothalamus was higher in HFD-O at different ages, peaking on day 28. Treatment with an m1mAChR agonist could modulate the inflammatory response in peripheral tissues. Specifically, CAP activation was greater in the liver of HFD-O following agonist treatment. Interestingly, lipopolysaccharide (LPS) challenge failed to induce a more inflammatory state in HFD-O, in contrast to SC-O, and agonist treatment had no additional effect. Analysis of spleen immune cells revealed a distinct phenotype in HFD-O, characterized by elevated levels of CD4+ lymphocytes rather than CD8+ lymphocytes. Moreover, basal Il17 messenger RNA (mRNA) levels were lower while Il22 mRNA levels were higher in HFD-O, and we observed the same pattern after LPS challenge. Further examination of myeloid cells isolated from bone marrow and allowed to differentiate showed that HFD-O macrophages displayed an anti-inflammatory phenotype. Additionally, treatment with the m1mAChR agonist contributed to reducing inflammatory marker levels in both groups. In summary, our findings demonstrate that HFD-O are protected against LPS-induced sepsis, and this protection is mediated by the central m1mAChR. Moreover, the inflammatory response in the liver, spleen, and bone marrow-differentiated macrophages is diminished. However, more extensive analysis is necessary to elucidate the specific mechanisms by which m1mAChR modulates the immune response during sepsis.
影响因子：
4.6
作者：
Martins ICA;Contieri LS;Amaral CL;Costa SO;Souza ACP;Ignacio-Souza LM;Milanski M;Torsoni AS;Torsoni MA
通讯作者：
Torsoni MA