Martínez Cristina, Latorre Jèssica, Ortega Francisco, Arnoriaga-Rodríguez María, Lluch Aina, Oliveras-Cañellas Núria, Díaz-Sáez Francisco, Aragonés Julian, Camps Marta, Gumà Anna, Ricart Wifredo, Fernández-Real José Manuel, Moreno-Navarrete José María
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona, Girona, Spain.
CIBEROBN (CB06/03/010), Instituto de Salud Carlos III, Madrid, Spain.
Front Physiol. 2022 Sep 15;13:950791. doi: 10.3389/fphys.2022.950791. eCollection 2022.
Neuregulin 4 (NRG4) has been described to improve metabolic disturbances linked to obesity status in rodent models. The findings in humans are controversial. We aimed to investigate circulating NRG4 in association with insulin action in humans and the possible mechanisms involved. Insulin sensitivity (euglycemic hyperinsulinemic clamp) and serum NRG4 concentration (ELISA) were analysed in subjects with a wide range of adiposity ( = 89). experiments with human HepG2 cell line were also performed. Serum NRG4 was negatively correlated with insulin sensitivity ( = -0.25, = 0.02) and positively with the inflammatory marker high-sensitivity C reative protein (hsCRP). In fact, multivariant linear regression analyses showed that insulin sensitivity contributed to BMI-, age-, sex-, and hsCRP-adjusted 7.2% of the variance in serum NRG4 ( = 0.01). No significant associations were found with adiposity measures (BMI, waist circumference or fat mass), plasma lipids (HDL-, LDL-cholesterol, or fasting triglycerides) or markers of liver injury. Cultured hepatocyte HepG2 treated with human recombinant NRG4 had an impact on hepatocyte metabolism, leading to decreased gluconeogenic- and mitochondrial biogenesis-related gene expression, and reduced mitochondrial respiration, without effects on expression of lipid metabolism-related genes. Similar but more pronounced effects were found after neuregulin 1 administration. In conclusion, sustained higher serum levels of neuregulin-4, observed in insulin resistant patients may have deleterious effects on metabolic and mitochondrial function in hepatocytes. However, findings from experiments should be confirmed in human primary hepatocytes.
在啮齿动物模型中，神经调节蛋白4（NRG4）已被证实可改善与肥胖状态相关的代谢紊乱。然而，其在人类中的研究结果存在争议。我们旨在研究人类循环中的NRG4与胰岛素作用之间的关系以及可能涉及的机制。对89名肥胖程度各异的受试者进行了胰岛素敏感性（正常血糖高胰岛素钳夹试验）和血清NRG4浓度（酶联免疫吸附测定法）分析。同时，也对人肝癌细胞系HepG2进行了实验。血清NRG4与胰岛素敏感性呈负相关（r = -0.25，P = 0.02），与炎症标志物高敏C反应蛋白（hsCRP）呈正相关。事实上，多变量线性回归分析表明，胰岛素敏感性对血清NRG4中经体重指数（BMI）、年龄、性别和hsCRP调整后的7.2%的方差有贡献（P = 0.01）。未发现与肥胖指标（BMI、腰围或脂肪量）、血脂（高密度脂蛋白胆固醇、低密度脂蛋白胆固醇或空腹甘油三酯）或肝损伤标志物有显著关联。用人重组NRG4处理培养的肝细胞HepG2会影响肝细胞代谢，导致糖异生和线粒体生物发生相关基因表达降低，线粒体呼吸减少，但对脂质代谢相关基因的表达无影响。给予神经调节蛋白1后发现了类似但更明显的效果。总之，在胰岛素抵抗患者中观察到的持续较高水平的神经调节蛋白4血清可能对肝细胞的代谢和线粒体功能产生有害影响。然而，细胞实验的结果应在人原代肝细胞中得到证实。
