Department of Neuropsychiatry, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
Department of Anatomy and Cell Biology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
J Transl Med. 2018 Nov 19;16(1):314. doi: 10.1186/s12967-018-1684-3.
The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis.
Il18 male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18 male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively.
Compared with Il18 mice, BAT of Il18 mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18 and Il18 mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18 BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18 and Il18 mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the 'Quantity of adipocytes' identified three associated genes, apolipoprotein C3 (Apoc3), insulin-induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes' size.
This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.
细胞因子白细胞介素-18（IL-18）最初被鉴定为一种干扰素-γ诱导的促炎因子；然而，越来越多的证据表明，它对生理功能具有非免疫作用。我们之前研究了 IL-18 与血脂异常、非酒精性脂肪肝和非酒精性脂肪性肝炎之间的潜在病理生理关系，这些关系是由脂质能量失衡介导的。因此，本文我们重点关注棕色脂肪细胞（BAs）和棕色脂肪组织（BAT），它们与能量消耗有关，是一种非颤抖性产热。
在 C57Bl/6 背景下生成 Il18 雄性小鼠，并用同窝 C57Bl/6 Il18 雄性小鼠作为对照。为了揭示 IL-18 的直接作用，我们从这两种小鼠中建立了原代细胞培养物。此外，为了进行分子分析，使用 6 周和 12 周龄的小鼠进行了微阵列、定量逆转录 PCR 和 Western blot 分析。为了评估 IL-18 对 BAT 的短期和长期影响，分别给予重组 IL-18 治疗 2 周和 12 周。
与 Il18 小鼠相比，Il18 小鼠的 BAT 显示出更早的分化和脂质积累。为了研究 IL-18 对 BAT 的直接作用，我们建立了 BA 细胞培养物。从 Il18 和 Il18 小鼠中提取出表达肌生成因子 5 的脂肪前体细胞。PR 结构域包含 16（PRDM16），一种分化诱导剂，在 Il18 BAs 中强烈表达，解偶联蛋白 1，一种产热和分化标志物，上调，促进 BA 分化。此外，激活了与 BAT 功能相关的 PRDM16 依赖性和非依赖性分子，如成纤维细胞生长因子 21。这些发现通过比较 6 周和 12 周龄的 Il18 和 Il18 小鼠得到了证实。对影响“脂肪细胞数量”的分子机制的进一步分析确定了三个相关基因，载脂蛋白 C3（Apoc3）、胰岛素诱导基因 1（Insig1）和维生素 D（1,25-二羟维生素 D3）受体（Vdr）。静脉注射 IL-18 不仅显著改善了其中一些基因的表达，而且还显著降低了脂肪细胞的大小。
本研究表明 IL-18 在 BAs 的分化和脂质代谢中具有关键功能。此外，IL-18 可能通过改善能量失衡来促进新的治疗方法。
