Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2-deficient (Lcn2^−/−) mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis, and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contribute to gain in adiposity in aged mice. Utilizing Lcn2^−/− mice and their wild-type (WT) littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6, and 9 mo old. Relative to WT mice, aged Lcn2^−/− mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in Lcn2^−/− mice by 6 mo of age. Interestingly, chow-fed Lcn2^−/− mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared with WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.

中文翻译：

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Lipocalin 2 缺乏引起的肠道微生物群失调引起老年小鼠的代谢综合征。

Lipocalin 2 (Lcn2) 是一种多功能先天免疫蛋白，可限制微生物过度生长。我们之前的研究表明肠道微生物群直接诱导肠道 Lcn2 的产生，而 Lcn2 缺陷（Lcn2 ^-/-）小鼠表现出肠道菌群失调。巧合的是，肠道菌群失调与代谢综合征发病机制有关，Lcn2 水平升高被认为是代谢综合征的潜在临床生物标志物。然而，Lcn2 是否减轻或加剧代谢综合征仍无定论。我们的目标是确定 Lcn2 缺乏引起的肠道微生物群的组成变化是否有助于老年小鼠肥胖。利用Lcn2 ^-/-对于小鼠及其野生型 (WT) 同窝仔鼠，我们测量了代谢标志物，包括空腹血糖、血脂、脂肪垫重量和 3、6 和 9 个月大时的胰岛素抵抗。相对于WT小鼠，老年Lcn2 ^-/-小鼠表现出与代谢综合征的许多特征相关的肥胖增加，包括胰岛素抵抗和血脂异常。令人惊讶的是，补充高脂肪饮食并没有进一步加重Lcn2 ^-/-小鼠 6 个月大时自发发生的代谢综合征。有趣的是，饲料喂养的Lcn2 ^-/-与 WT 小鼠相比，小鼠在肠道微生物群的细菌丰度和代谢组学特征方面表现出显着差异。总的来说，我们的结果表明 Lcn2 对于维持代谢和肠道微生物稳态至关重要，其中缺乏会导致代谢综合征的自发延迟发作。