Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Av. Diagonal 643, 08028 Barcelona, Spain.
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona (UB), 08028 Barcelona, Spain.
Int J Mol Sci. 2024 Oct 31;25(21):11718. doi: 10.3390/ijms252111718.
Neuregulin 4 (Nrg4) is an adipokine that belongs to the epidermal growth factor family and binds to ErbB4 tyrosine kinase receptors. In 3T3-L1 adipocytes, the downregulation of expression enhances inflammation and autophagy, resulting in insulin resistance. Here, we searched for the causes of this phenotype. Nrg4 knockdown (Nrg4 KD) adipocytes showed a significant reduction in mitochondrial content and elongation, along with a lower content of the mitochondria fusion protein mitofusin 2 (MFN2), and increased HO production compared to the control scrambled cells (Scr). The antioxidant N-acetylcysteine reversed the oxidative stress and reduced the gene expression of the pro-inflammatory cytokine tumor necrosis factor α (TNFα). Nrg4 KD adipocytes showed enhanced lipolysis and reduced lipogenesis, in addition to a significant reduction in several intermediates of the Krebs cycle. In summary, Nrg4 downregulation in adipocytes affects mitochondrial content and functioning, causing impaired cellular metabolism, which in turn results in oxidative stress, inflammation, and insulin resistance.
神经调节蛋白 4（Nrg4）是一种脂肪因子，属于表皮生长因子家族，能与 ErbB4 酪氨酸激酶受体结合。在 3T3-L1 脂肪细胞中，下调表达可增强炎症和自噬，导致胰岛素抵抗。在这里，我们寻找这种表型的原因。与对照 scrambled 细胞（Scr）相比，Nrg4 敲低（Nrg4 KD）脂肪细胞的线粒体含量和伸长明显减少，线粒体融合蛋白 mitofusin 2（MFN2）的含量较低，HO 生成增加。抗氧化剂 N-乙酰半胱氨酸可逆转氧化应激并降低促炎细胞因子肿瘤坏死因子α（TNFα）的基因表达。Nrg4 KD 脂肪细胞表现出增强的脂肪分解和减少的脂肪生成，此外，三羧酸循环的几个中间产物显著减少。总之，脂肪细胞中 Nrg4 的下调会影响线粒体的含量和功能，导致细胞代谢受损，进而导致氧化应激、炎症和胰岛素抵抗。
