Background Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. Results Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1 -/- ) mice. Conclusions These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.

中文翻译：

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SerpinA3N 是一种新的下丘脑基因，在小鼠中被高脂饮食和瘦素上调。

背景能量稳态由下丘脑调节，但当动物被喂食高脂肪饮食 (HFD) 时会失败，并且会出现瘦素不敏感和肥胖。为了阐明这些影响的可能机制，基于微阵列的转录组学方法被用于鉴定小鼠下丘脑中受 HFD 和瘦素调节的新基因。结果 小鼠全局阵列数据将 serpinA3N 鉴定为受 HFD 和瘦素攻击高度上调的新基因。原位杂交显示 HFD 和瘦素在所有主要的下丘脑核中上调 serpinA3N 表达，这与转录组基因表达数据一致。下丘脑克隆神经元细胞系 mHypoE-N42 (N42) 的免疫组织化学和研究证实，由 serpinA3 编码的蛋白质 α 1-抗胰凝乳蛋白酶 (α1AC)，定位于神经元并显示它被分泌到媒体中。N42 神经元中的 SerpinA3N 表达被棕榈酸和瘦素以及 IL-6 和 TNFα 上调，所有三个基因都被抗炎单不饱和脂肪油酸下调。此外，NFκB 抑制剂 BAY11 阻断了 N42 神经元中 serpinA3 的棕榈酸酯上调，并且在 IL-1 受体 1 敲除 (IL-1R1 -/- ) 小鼠中，HFD 对下丘脑中 serpinA3N 表达的上调减弱。结论 这些数据表明，serpinA3 表达与营养介导的下丘脑炎症有关。并且所有三个基因都被抗炎单不饱和脂肪油酸下调。此外，NFκB 抑制剂 BAY11 阻断了 N42 神经元中 serpinA3 的棕榈酸酯上调，并且在 IL-1 受体 1 敲除 (IL-1R1 -/- ) 小鼠中，HFD 对下丘脑中 serpinA3N 表达的上调减弱。结论 这些数据表明，serpinA3 表达与营养介导的下丘脑炎症有关。并且所有三个基因都被抗炎单不饱和脂肪油酸下调。此外，NFκB 抑制剂 BAY11 阻断了 N42 神经元中 serpinA3 的棕榈酸酯上调，并且在 IL-1 受体 1 敲除 (IL-1R1 -/- ) 小鼠中，HFD 对下丘脑中 serpinA3N 表达的上调减弱。结论 这些数据表明，serpinA3 表达与营养介导的下丘脑炎症有关。