Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIR-KO, fat-specific IGF-1 receptor and insulin receptor–KO) exhibit complete loss of white and brown adipose tissue (WAT and BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIR-KO mice with fat-specific KO of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint–KO). Unlike FIGIR-KO mice, F-Quint–KO mice had normal BAT, glucose tolerance, insulin-regulated hepatic glucose production, and cold tolerance. However, loss of FOXOs only partially rescued subcutaneous WAT and hepatosteatosis, did not rescue perigonadal WAT or systemic insulin resistance, and led to even more marked hyperinsulinemia. Thus, FOXOs play different roles in insulin/IGF-1 action in different adipose depots, being most important in BAT, followed by subcutaneous WAT and then by visceral WAT. Disruption of FOXOs in fat also led to a reversal of insulin resistance in liver, but not in skeletal muscle, and an exacerbation of hyperinsulinemia. Thus, adipose FOXOs play a unique role in regulating crosstalk between adipose depots, liver, and β cells.

中文翻译：

---

FOXO 转录因子对棕色和白色脂肪组织中胰岛素作用的不同作用

胰岛素和 IGF-1 对脂肪细胞的分化和功能至关重要。脂肪中缺乏胰岛素和 IGF-1 受体（FIGIR-KO、f at 特异性IG F-1 受体和胰岛素受体– KO）的小鼠表现出白色和棕色脂肪组织（WAT 和 BAT）完全丧失、葡萄糖耐受不良、胰岛素抵抗、肝脂肪变性和冷不耐受。为了确定 FOXO 转录因子在脂肪表型改变中的作用，我们生成了具有脂肪表达Foxo s [ Foxo1、Foxo3、Foxo4的脂肪特异性 KO 的 FIGIR-KO 小鼠]（F-Quint-KO）。与 FIGIR-KO 小鼠不同，F-Quint-KO 小鼠具有正常的 BAT、葡萄糖耐量、胰岛素调节的肝葡萄糖生成和耐寒性。然而，FOXOs 的缺失只能部分挽救皮下 WAT 和肝脂肪变性，不能挽救性腺周围 WAT 或全身胰岛素抵抗，并导致更明显的高胰岛素血症。因此，FOXO 在不同脂肪库中的胰岛素/IGF-1 作用中发挥不同作用，在 BAT 中最重要，其次是皮下 WAT，然后是内脏 WAT。脂肪中 FOXO 的破坏也导致肝脏胰岛素抵抗的逆转，但骨骼肌中的胰岛素抵抗没有逆转，并导致高胰岛素血症恶化。因此，脂肪 FOXO 在调节脂肪库、肝脏和 β 细胞之间的串扰中发挥着独特的作用。