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Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels
Nature Communications ( IF 14.7 ) Pub Date : 2024-05-30 , DOI: 10.1038/s41467-024-48220-5
Shuai Yan 1, 2 , Anna Santoro 1, 2 , Micah J Niphakis 3 , Antonio M Pinto 4 , Christopher L Jacobs 1, 2 , Rasheed Ahmad 5 , Radu M Suciu 3 , Bryan R Fonslow 3 , Rachel A Herbst-Graham 3 , Nhi Ngo 3 , Cassandra L Henry 3 , Dylan M Herbst 3 , Alan Saghatelian 4 , Barbara B Kahn 1, 2, 6 , Evan D Rosen 1, 2, 6
Affiliation  

Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.



中文翻译:


炎症通过干扰素调节因子 3 (IRF3) 介导的 FAHFA 水平降低导致小鼠胰岛素抵抗



肥胖诱导的炎症会导致代谢功能障碍,但机制仍然难以捉摸。在这里,我们表明先天免疫转录因子干扰素调节因子 (IRF3) 通过诱导脂肪细胞中内源性 FAHFA 水解酶雄激素诱导基因 1 (AIG1) 对葡萄糖稳态产生不利影响。脂肪细胞特异性敲除 IRF3 可保护雄性小鼠免受高脂饮食诱导的胰岛素抵抗,而脂肪细胞中 IRF3 或 AIG1 的过表达会促进高脂饮食中的胰岛素抵抗。此外,在脂肪细胞 IRF3 过表达的情况下,AIG1 的药理学抑制逆转了肥胖诱导的胰岛素抵抗并恢复了葡萄糖稳态。因此,我们将脂肪细胞 IRF3/AIG1 轴确定为肥胖诱导的炎症和胰岛素抵抗之间的关键联系,并提出了一种限制肥胖伴随代谢功能障碍的方法。

更新日期:2024-05-30
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