Epigenetic regulation of brown fat thermogenesis by the histone demethylase KDM6A

肥胖是由于能量摄入超过能量消耗而导致的能量稳态失调。适应性产热，其中棕色脂肪组织（BAT）的功能，以散热的能量，是整体能量消耗的一个组成部分。肥胖是一种基因与环境相互作用的复杂疾病。饮食等环境因素影响基因表达模式的机制之一涉及它们重编程表观基因组的能力。证据表明，表观遗传事件，包括组蛋白甲基化，在肥胖的发展中起着重要作用。赖氨酸（K）特异性脱甲基酶6A（KDM 6A）是一种组蛋白脱甲基酶，其优先使三甲基化的组蛋白赖氨酸27（H3 K27 me 3）脱甲基，因此减轻其沉默基因的能力，导致基因转录的激活。我们发表的和初步的数据表明，KDM 6A在调节棕色脂肪产热程序，能量代谢和饮食诱导的肥胖症（DIO）中是重要的，并且KDM 6A过表达增加BAT衍生的神经营养因子神经营养因子3（NT 3）的表达和分泌，其增强交感神经系统（SNS）神经支配脂肪组织。因此，我们假设KDM 6A在调节棕色脂肪产热、能量代谢和肥胖中起重要作用，并且KDM 6A刺激的NT 3（BAT衍生的神经营养因子）通过增强SNS神经支配促进棕色/米色细胞产热。目的1在遗传模型中确定KDM 6A在冷诱导的产热、能量代谢和饮食诱导的肥胖中的作用。我们将使用棕色脂肪KDM 6A缺陷或过表达小鼠（分别命名为AKO和AOE小鼠）来确定棕色脂肪中KDM 6A的特异性缺失是否会在冷暴露期间损害棕色脂肪产热并促进饮食诱导的肥胖，而棕色脂肪中KDM 6A的特异性过表达则相反。O-GlcNAc酰化已成为一种关键的营养传感器，可调节细胞代谢途径，以响应营养过度的提示（例如过量的葡萄糖和脂肪酸）。我们将确定是否KDM 6A O-GlcNAc酰化过量的营养物质（葡萄糖和脂肪酸）降低其能力去甲基化H3 K27 me 3在产热基因启动子，从而损害饮食诱导的产热。目的2研究KDMK 6A刺激的NT 3（一种棕色脂肪源性神经营养因子）通过交感神经支配进入脂肪组织，在调节适应性产热、能量代谢和饮食诱导的肥胖中的作用。我们已经产生了脂肪细胞特异性过表达NT 3的小鼠。我们将确定1）NT 3的脂肪过表达是否促进冷诱导的产热并防止饮食诱导的肥胖; 2）NT 3是否通过激活其受体原肌球蛋白受体激酶C（TRKC）刺激SNS神经支配进入脂肪组织和交感神经元轴突生长; 3）NT 3是否或在多大程度上介导KDM 6A在促进棕色/米色细胞产热和防止DIO中的作用。该项目的完成有助于指导KDM 6A和NT 3作为治疗肥胖症的新靶点的开发。

Obesity is a disorder of energy homeostasis due to energy intake over energy expenditure. Adaptive thermogenesis, in which brown adipose tissue (BAT) functions to dissipate energy as heat, is an integral part of overall energy expenditure. Obesity is a complex disease resulting from gene and environment interactions. One of the mechanisms that environmental factors such as diets affect gene expression patterns involves their capacity to reprogram the epigenome. Evidence converges to suggest that epigenetic events, including histone methylation, figure prominently in the development of obesity. Lysine (K) specific demethylase 6A (KDM6A) is a histone demethylase that preferentially demethylates tri-methylated histone lysine 27 (H3K27me3) and therefore relieves its ability to silence the genes, leading to activation of the gene transcription. Our published and preliminary data suggest that KDM6A is important in regulating brown fat thermogenic program, energy metabolism and diet-induced obesity (DIO), and that KDM6A overexpression increases the expression and secretion of a BAT-derived neurotrophic factor neurotrophin 3 (NT3), which enhances sympathetic nervous system (SNS) innervation into adipose tissue. Therefore, we hypothesize that KDM6A plays an important role in regulating brown fat thermogenesis, energy metabolism and obesity, and that KDM6A-stimulated NT3, a BAT-derived neurotropic factor, promotes brown/beige cell thermogenesis via enhanced SNS innervation. Aim 1 will determine the role of KDM6A in cold-induced thermogenesis, energy metabolism and diet-induced obesity in genetic models. We will use brown fat KDM6A deficient or overexpressing mice (named AKO and AOE mice, respectively) to determine whether specific deletion of KDM6A in brown fat impairs brown fat thermogenesis during cold exposure and promotes diet-induced obesity, whereas specific overexpression of KDM6A in brown fat does the opposite. O-GlcNAcylation has emerged as a key nutrient sensor that regulates cellular metabolic pathways in response to overnutritional cues (e.g. excess glucose and fatty acids). We will determine whether KDM6A O-GlcNAcylation by excess nutrients (glucose and fatty acids) decreases its ability to demethylate H3K27me3 at the thermogenic gene promoters, thereby compromising diet-induced thermogenesis. Aim 2 will investigate the role of KDMK6A-stimulated NT3, a brown fat-derived neurotropic factor, in regulating adaptive thermogenesis, energy metabolism and diet-induced obesity, via sympathetic innervation into adipose tissue. We have generated mice with adipocyte-specific overexpression of NT3. We will determine 1) whether adipose overexpression of NT3 promotes cold-induced thermogenesis and prevents diet-induced obesity; 2) whether NT3 stimulates SNS innervation into adipose tissue and sympathetic neuron axonal growth via activating its receptor tropomyosin receptor kinase C (TRKC); 3) whether or to what extent NT3 mediates the effect of KDM6A in promoting brown/beige cell thermogenesis and preventing DIO. Completion of this project could help guide the development of KDM6A and NT3 as new therapeutic targets in the treatment of obesity.