Dunn Tamara N, Akiyama Tasuku, Lee Hyun Woo, Kim Jae Bum, Knotts Trina A, Smith Steven R, Sears Dorothy D, Carstens Earl, Adams Sean H
Graduate Group in Nutritional Biology, University of California Davis, Davis, California, United States of America; Department of Nutrition, University of California Davis, Davis, California, United States of America.
Department of Neurobiology, Physiology and Behavior, University of California Davis, Davis, California, United States of America.
PLoS One. 2015 Mar 10;10(3):e0115830. doi: 10.1371/journal.pone.0115830. eCollection 2015.
Recent evidence in adipocytes points to a role for synuclein-γ in metabolism and lipid droplet dynamics, but interestingly this factor is also robustly expressed in peripheral neurons. Specific regulation of the synuclein-γ gene (Sncg) by PPARγ requires further evaluation, especially in peripheral neurons, prompting us to test if Sncg is a bona fide PPARγ target in murine adipocytes and peripheral somatosensory neurons derived from the dorsal root ganglia (DRG). Sncg mRNA was decreased in 3T3-L1 adipocytes (68%) by rosiglitazone, and this effect was diminished by the PPARγ antagonist T0070907. Chromatin immunoprecipitation experiments confirmed PPARγ protein binding at two promoter sequences of Sncg during 3T3-L1 adipogenesis. Rosiglitazone did not affect Sncg mRNA expression in murine cultured DRG neurons. In subcutaneous human WAT samples from two cohorts treated with pioglitazone (>11 wks), SNCG mRNA expression was reduced, albeit highly variable and most evident in type 2 diabetes. Leptin (Lep) expression, thought to be coordinately-regulated with Sncg based on correlations in human adipose tissue, was also reduced in 3T3-L1 adipocytes by rosiglitazone. However, Lep was unaffected by PPARγ antagonist, and the LXR agonist T0901317 significantly reduced Lep expression (64%) while not impacting Sncg. The results support the concept that synuclein-γ shares some, but not all, gene regulators with leptin and is a PPARγ target in adipocytes but not DRG neurons. Regulation of synuclein-γ by cues such as PPARγ agonism in adipocytes is logical based on recent evidence for an important role for synuclein-γ in the maintenance and dynamics of adipocyte lipid droplets.
近期在脂肪细胞中的证据表明，突触核蛋白γ在代谢和脂滴动态变化中发挥作用，但有趣的是，该因子在外周神经元中也有大量表达。过氧化物酶体增殖物激活受体γ（PPARγ）对突触核蛋白γ基因（Sncg）的特异性调控需要进一步评估，尤其是在外周神经元中，这促使我们测试Sncg在小鼠脂肪细胞和源自背根神经节（DRG）的外周体感神经元中是否为真正的PPARγ靶标。罗格列酮使3T3-L1脂肪细胞中的Sncg mRNA减少了约68%，并且PPARγ拮抗剂T0070907减弱了这种作用。染色质免疫沉淀实验证实，在3T3-L1脂肪生成过程中，PPARγ蛋白结合在Sncg的两个启动子序列上。罗格列酮不影响小鼠培养的DRG神经元中Sncg mRNA的表达。在接受吡格列酮治疗（>11周）的两个队列的皮下人体白色脂肪组织样本中，SNCG mRNA表达降低，尽管变化很大，且在2型糖尿病中最为明显。基于人体脂肪组织中的相关性，人们认为瘦素（Lep）表达与Sncg协同调节，罗格列酮也使3T3-L1脂肪细胞中的Lep表达降低。然而，Lep不受PPARγ拮抗剂影响，而肝X受体激动剂T0901317显著降低Lep表达（约64%），同时不影响Sncg。这些结果支持了这样一种观点，即突触核蛋白γ与瘦素共享一些但并非全部的基因调节因子，并且在脂肪细胞中是PPARγ的靶标，但在DRG神经元中不是。基于近期突触核蛋白γ在脂肪细胞脂滴维持和动态变化中起重要作用的证据，脂肪细胞中诸如PPARγ激动等信号对突触核蛋白γ的调节是合理的。
