Li Xinzhong, Thomason Peter A, Withers Dominic J, Scott James
National Heart and Lung Institute, Medicine Department, Imperial College London, South Kensington, Exhibition Road, London SW7 2AZ, UK.
BMC Syst Biol. 2010 Dec 27;4:175. doi: 10.1186/1752-0509-4-175.
Obesity causes insulin resistance in target tissues - skeletal muscle, adipose tissue, liver and the brain. Insulin resistance predisposes to type-2 diabetes (T2D) and cardiovascular disease (CVD). Adipose tissue inflammation is an essential characteristic of obesity and insulin resistance. Neuronatin (Nnat) expression has been found to be altered in a number of conditions related to inflammatory or metabolic disturbance, but its physiological roles and regulatory mechanisms in adipose tissue, brain, pancreatic islets and other tissues are not understood.
We identified transcription factor binding sites (TFBS) conserved in the Nnat promoter, and transcription factors (TF) abundantly expressed in adipose tissue. These include transcription factors concerned with the control of: adipogenesis (Pparγ, Klf15, Irf1, Creb1, Egr2, Gata3); lipogenesis (Mlxipl, Srebp1c); inflammation (Jun, Stat3); insulin signalling and diabetes susceptibility (Foxo1, Tcf7l2). We also identified NeuroD1 the only documented TF that controls Nnat expression. We identified KEGG pathways significantly associated with Nnat expression, including positive correlations with inflammation and negative correlations with metabolic pathways (most prominently oxidative phosphorylation, glycolysis and gluconeogenesis, pyruvate metabolism) and protein turnover. 27 genes, including; Gstt1 and Sod3, concerned with oxidative stress; Sncg and Cxcl9 concerned with inflammation; Ebf1, Lgals12 and Fzd4 involved in adipogenesis; whose expression co-varies with Nnat were identified, and conserved transcription factor binding sites identified on their promoters. Functional networks relating to each of these genes were identified.
Our analysis shows that Nnat is an acute diet-responsive gene in white adipose tissue and hypothalamus; it may play an important role in metabolism, adipogenesis, and resolution of oxidative stress and inflammation in response to dietary excess.
肥胖会导致靶组织（骨骼肌、脂肪组织、肝脏和大脑）出现胰岛素抵抗。胰岛素抵抗易引发2型糖尿病（T2D）和心血管疾病（CVD）。脂肪组织炎症是肥胖和胰岛素抵抗的一个重要特征。已发现神经元正五聚蛋白（Nnat）的表达在一些与炎症或代谢紊乱相关的情况下会发生改变，但其在脂肪组织、大脑、胰岛及其他组织中的生理作用和调控机制尚不清楚。
我们确定了Nnat启动子中保守的转录因子结合位点（TFBS），以及在脂肪组织中大量表达的转录因子（TF）。这些转录因子包括与以下方面控制有关的因子：脂肪生成（过氧化物酶体增殖物激活受体γ（Pparγ）、 Kruppel样因子15（Klf15）、干扰素调节因子1（Irf1）、环磷腺苷效应元件结合蛋白1（Creb1）、早期生长反应蛋白2（Egr2）、GATA结合蛋白3（Gata3））；脂质生成（Max-like转录激活因子相互作用蛋白（Mlxipl）、固醇调节元件结合蛋白1c（Srebp1c））；炎症（Jun、信号转导和转录激活因子3（Stat3））；胰岛素信号传导和糖尿病易感性（叉头框蛋白O1（Foxo1）、T细胞因子7样蛋白2（Tcf7l2））。我们还确定了神经分化因子1（NeuroD1）是唯一有文献记载的控制Nnat表达的转录因子。我们确定了与Nnat表达显著相关 的京都基因与基因组百科全书（KEGG）通路，包括与炎症的正相关以及与代谢通路（最显著的是氧化磷酸化、糖酵解和糖异生、丙酮酸代谢）和蛋白质周转的负相关。确定了27个基因，包括与氧化应激有关的谷胱甘肽S-转移酶θ1（Gstt1）和超氧化物歧化酶3（Sod3）；与炎症有关的突触核蛋白γ（Sncg）和CXC趋化因子9（Cxcl9）；参与脂肪生成的早期B细胞因子1（Ebf1）、半乳糖凝集素12（Lgals12）和卷曲蛋白4（Fzd4），其表达与Nnat共同变化，并在其启动子上确定了保守的转录因子结合位点。确定了与这些基因各自相关的功能网络。
我们的分析表明，Nnat是白色脂肪组织和下丘脑中一种对饮食急性反应的基因；它可能在代谢、脂肪生成以及应对饮食过量时氧化应激和炎症的消退中发挥重要作用。
