Arachidonic acid sex-dependently affects obesity through linking gut microbiota-driven inflammation to hypothalamus-adipose-liver axis
Arachidonic acid sex-dependently affects obesity through linking gut microbiota-driven inflammation to hypothalamus-adipose-liver axis
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花生四烯酸通过将肠道微生物群驱动的炎症与下丘脑-脂肪肝轴联系起来，对肥胖产生性别依赖性影响
DOI：
10.1016/j.bbadis.2017.07.003
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发表时间：
2017-11-01
影响因子：
6.2
通讯作者：
Zhang, Yu
中科院分区：
文献类型：
--
作者：
Zhuang, Pan;Shou, Qiyang;Zhang, Yu
揭示膳食脂质的作用有利于治疗肥胖和代谢功能障碍。尽管如此，饮食中的血脂如何影响现有的肥胖症仍是个未知数。花生四烯酸(AA)是亚油酸的衍生物，是重要的n-6脂肪酸之一。这项研究的目的是调查AA是否通过将微生物区系驱动的炎症与下丘脑-脂肪-肝轴联系起来影响肥胖。4周龄C57BL/6J小鼠以高脂饲料(HFD，45%脂肪)喂养10周，诱导肥胖，然后在接下来的15周内喂以富含10g/kg AA的HFD或连续给予HFD。研究对象包括全身性肥胖与炎症、代谢特征、肠道微生物区系组成、短链脂肪酸生成、下丘脑摄食调节剂、脂肪细胞褐变过程、肝性骨病和脂肪中的胰岛素抵抗。结果表明，AA加重了男女的肥胖，而性别对肠道微生物区系组成有影响。此外，AA有利于促炎微生物区系，减少丁酸的产生和循环中的5-羟色胺，这会加剧全球炎症，并通过小胶质细胞在男性体内积累来触发下丘脑瘦素抵抗。AA通过TLR4-NF-kappaB途径加重非酒精性脂肪性肝炎和放大炎症，并诱导胰岛素抵抗。相反，AA通过拯救抗炎和产生丁酸的微生物区系，上调Gpr41和Gpr109a，以及控制女性下丘脑炎症来缓解肥胖相关的疾病。然而，AA改善了脂肪细胞的褐变，促进了两性的脂肪动员。我们发现AA可能通过肠道-下丘脑-脂肪-肝轴影响肥胖。我们的发现从肥胖受试者的饮食摄入量中提出了n-6脂肪酸的建议，如AA，最好是以性别二态的方式。
Unraveling the role of dietary lipids is beneficial to treat obesity and metabolic dysfunction. Nonetheless, how dietary lipids affect existing obesity remains unknown. Arachidonic acid (AA), a derivative of linoleic acid, is one of the crucial n-6 fatty acids. The aim of this study was to investigate whether AA affects obesity through associating microbiota-driven inflammation with hypothalamus-adipose-liver axis. Four-week old C57BL/6 J mice were fed with a high-fat diet (HFD, 45% fat) for 10 weeks to induce obesity, and then fed a HFD enriched with 10 g/kg of AA or a continuous HFD in the following 15 weeks. Systemic adiposity and inflammation, metabolic profiles, gut microbiota composition, short-chain fatty acids production, hypothalamic feeding regulators, browning process of adipocytes, hepatosteatosis, and insulin resistance in adipose were investigated. The results indicated that AA aggravates obesity for both genders whereas sex-dependently affects gut microbiota composition. Also, AA favors pro-inflammatory microbiota and reduces butyrate production and circulating serotonin, which augments global inflammation and triggers hypothalamic leptin resistance via microglia accumulation in male. AA exacerbates non-alcoholic steatohepatitis along with amplified inflammation through TLR4-NF-kappa B pathway and induces insulin resistance. Reversely, AA alleviates obesity-related disorders via rescuing anti-inflammatory and butyrate-producing microbiota, up-regulating GPR41 and GPR109A and controlling hypothalamic inflammation in female. Nevertheless, AA modifies adipocyte browning and promotes lipid mobilization for both genders. We show that AA affects obesity likely through a gut-hypothalamus-adipose-liver axis. Our findings formulate recommendations of n-6 fatty acids like AA from dietary intake for obese subjects preferably in a sexually dimorphic way.