Departments of Physiology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Department of Surgery, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Cells. 2024 Oct 5;13(19):1654. doi: 10.3390/cells13191654.
The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis. However, much remains unknown about its role in adipogenesis. Here, we demonstrated that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Inhibition of neddylation by MLN4924 significantly reduced adipogenesis of 3T3-L1 and human stromal vascular cells. Deletion of NAE1, a subunit of the only NEDD8 E1 enzyme, suppressed neddylation and impaired adipogenesis. Neddylation deficiency did not affect mitotic cell expansion. Instead, it disrupted CREB/CEBPβ/PPARγ signaling, essential for adipogenesis. Interestingly, among the neddylation-targeted CUL family members, deletion of CUL3, but not CUL1, CUL2, or CUL4A, largely replicated the adipogenic defects observed with neddylation deficiency. A PPARγ agonist minimally rescued the adipogenic defects caused by the deletion of NAE1 and CUL3. In conclusion, our study demonstrates that neddylation and its targeted CUL3 are crucial for adipogenesis. These findings provide potential targets for therapeutic intervention in obesity and metabolic disorders.
目前肥胖症的流行已经引起了人们对脂肪组织复杂生理学的关注。异常的脂肪细胞分化会导致全身性代谢紊乱的发展，如胰岛素抵抗和糖尿病。NEDD8（神经前体细胞表达，发育下调 8）与靶蛋白的缀合，称为 neddylation，已被证明介导脂肪生成。然而，关于其在脂肪生成中的作用，仍有许多未知之处。在这里，我们证明了 neddylation 及其靶标，CUL（cullin）家族成员，在小鼠和人类脂肪生成过程中是不同调节的。通过 MLN4924 抑制 neddylation 可显著减少 3T3-L1 和人基质血管细胞的脂肪生成。NEDD8 E1 酶唯一亚基 NAE1 的缺失抑制了 neddylation 并损害了脂肪生成。Neddylation 缺陷并不影响有丝分裂细胞的扩张。相反，它破坏了 CREB/CEBPβ/PPARγ 信号通路，这对脂肪生成至关重要。有趣的是，在 neddylation 靶向的 CUL 家族成员中，CUL3 的缺失，而不是 CUL1、CUL2 或 CUL4A 的缺失，很大程度上复制了与 neddylation 缺陷观察到的脂肪生成缺陷。PPARγ 激动剂最小程度地挽救了 NAE1 和 CUL3 缺失引起的脂肪生成缺陷。总之，我们的研究表明 neddylation 及其靶向 CUL3 对脂肪生成至关重要。这些发现为肥胖症和代谢紊乱的治疗干预提供了潜在的靶点。
