White adipose tissue (WAT) plays a role in storing energy, while brown adipose tissue (BAT) is instrumental in the re-distribution of stored energy when dietary sources are unavailable. Interleukin-18 (IL18) is a cytokine playing a role in T-cell polarization, but also for regulating energy homeostasis via the dimeric IL18 receptor (IL18r) and Na-Cl co-transporter (NCC) on adipocytes. Here we show that IL18 signaling in metabolism is regulated at the level of receptor utilization, with preferential role for NCC in brown adipose tissue (BAT) and dominantly via IL18r in WAT. In Il18r^−/−Ncc^−/− mice, high-fat diet (HFD) causes more prominent body weight gain and insulin resistance than in wild-type mice. The WAT insulin resistance phenotype of the double-knockout mice is recapitulated in HFD-fed Il18r^−/− mice, whereas decreased thermogenesis in BAT upon HFD is dependent on NCC deletion. BAT-selective depletion of either NCC or IL18 reduces thermogenesis and increases BAT and WAT inflammation. IL18r deletion in WAT reduces insulin signaling and increases WAT inflammation. In summary, our study contributes to the mechanistic understanding of IL18 regulation of energy metabolism and shows clearly discernible roles for its two receptors in brown and white adipose tissues.

白色脂肪组织 (WAT) 在储存能量方面发挥作用，而棕色脂肪组织 (BAT) 在饮食来源不可用时有助于重新分配储存的能量。白介素 18 (IL18) 是一种细胞因子，在 T 细胞极化中发挥作用，但也通过脂肪细胞上的二聚体 IL18 受体 (IL18r) 和 Na-Cl 共转运蛋白 (NCC) 调节能量稳态。在这里，我们表明代谢中的 IL18 信号在受体利用水平上受到调节，其中 NCC 在棕色脂肪组织 (BAT) 中起优先作用，而在 WAT 中主要通过 IL18r 发挥作用。在Il18r ^−/− Ncc ^−/−在小鼠中，高脂肪饮食（HFD）导致比野生型小鼠更显着的体重增加和胰岛素抵抗。双敲除小鼠的 WAT 胰岛素抵抗表型在 HFD 喂养的Il18r ^-/−小鼠中得到重现，而 HFD 后 BAT 生热作用的降低取决于 NCC 缺失。BAT 选择性消耗 NCC 或 IL18 会减少生热作用并增加 BAT 和 WAT 炎症。WAT 中 IL18r 缺失会减少胰岛素信号传导并增加 WAT 炎症。总之，我们的研究有助于理解 IL18 能量代谢调节的机制，并显示出其两种受体在棕色和白色脂肪组织中的清晰可辨的作用。