Genzer Yoni, Chapnik Nava, Froy Oren
Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
Int J Biochem Cell Biol. 2017 Jul;88:69-74. doi: 10.1016/j.biocel.2017.05.008. Epub 2017 May 5.
Brain-derived neurotrophic factor (BDNF) plays crucial roles in the development, maintenance, plasticity and homeostasis of the central and peripheral nervous systems. Perturbing BDNF signaling in mouse brain results in hyperphagia, obesity, hyperinsulinemia and hyperglycemia. Currently, little is known whether BDNF affects liver tissue directly. Our aim was to determine the metabolic signaling pathways activated after BDNF treatment in hepatocytes. Unlike its effect in the brain, BDNF did not lead to activation of the liver AKT pathway. However, AMP protein activated kinase (AMPK) was ∼3 times more active and fatty acid synthase (FAS) ∼2-fold less active, suggesting increased fatty acid oxidation and reduced fatty acid synthesis. In addition, cAMP response element binding protein (CREB) was ∼3.5-fold less active together with its output the gluconeogenic transcript phosphoenolpyruvate carboxykinase (Pepck), suggesting reduced gluconeogenesis. The levels of glycogen synthase kinase 3b (GSK3b) was ∼3-fold higher suggesting increased glycogen synthesis. In parallel, the expression levels of the clock genes Bmal1 and Cry1, whose protein products play also a metabolic role, were ∼2-fold increased and decreased, respectively. In conclusion, BDNF binding to hepatocytes leads to activation of catabolic pathways, such as fatty acid oxidation. In parallel gluconeogenesis is inhibited, while glycogen storage is triggered. This metabolic state mimics that of after breakfast, in which the liver continues to oxidize fat, stops gluconeogenesis and replenishes glycogen stores.
脑源性神经营养因子（BDNF）在中枢和外周神经系统的发育、维持、可塑性和稳态中发挥着关键作用。扰乱小鼠脑中的BDNF信号会导致食欲亢进、肥胖、高胰岛素血症和高血糖。目前，关于BDNF是否直接影响肝脏组织知之甚少。我们的目的是确定肝细胞经BDNF处理后激活的代谢信号通路。与它在脑中的作用不同，BDNF不会导致肝脏AKT通路的激活。然而，AMP蛋白激活激酶（AMPK）的活性约高3倍，脂肪酸合酶（FAS）的活性约低2倍，这表明脂肪酸氧化增加而脂肪酸合成减少。此外，cAMP反应元件结合蛋白（CREB）及其输出的糖异生转录本磷酸烯醇式丙酮酸羧激酶（Pepck）的活性约低3.5倍，这表明糖异生减少。糖原合酶激酶3b（GSK3b）的水平约高3倍，表明糖原合成增加。同时，时钟基因Bmal1和Cry1的表达水平分别约增加2倍和降低2倍，其蛋白质产物也发挥代谢作用。总之，BDNF与肝细胞结合会导致分解代谢途径的激活，如脂肪酸氧化。同时，糖异生受到抑制，而糖原储存被触发。这种代谢状态类似于早餐后的状态，即肝脏继续氧化脂肪、停止糖异生并补充糖原储备。
