Epigenetic mechanisms underlying sex differences in obesity

项目总结 女性和男性脂肪组织的生理和功能特性不同，这 导致肥胖和代谢综合征风险在性别之间的差异。而性腺激素 造成这些生理性别差异的原因，Reue实验室已经证明了XX或XY的存在 性染色体以性别依赖的方式进一步影响脂肪的发育和功能。具体来说， 与XY动物相比，两条X染色体的存在会导致更高的体重和肥胖。什么时候 存在两条X染色体，一条X染色体上的基因被失活以使基因表达正常化 XY细胞。然而，这些X染色体基因的一部分逃脱了失活，导致在 XX细胞与XY细胞的比较。这导致了一个假设，即较高的X染色体基因剂量会影响 肥胖症的性别差异。我们发现了影响肥胖的两个X染色体基因，Kdm5c和Kdm6a 在体内，分别通过改变前脂肪细胞和成熟脂肪细胞的细胞功能。Kdm5c基因的还原 前脂肪细胞的剂量降低了成熟期的体重和肥胖，同时减少了Kdm5c基因的剂量。 脂肪细胞对体重或肥胖没有影响。相反，Kdm6a基因在成熟期的剂量减少 脂肪细胞可以减轻体重和肥胖。Kdm5c和Kdm6a都编码组蛋白去甲基酶 通过改变染色质结构来调节整个基因组的基因表达。因此，以下各项的综合行动 前脂肪细胞中的KDM5C和成熟脂肪细胞中的KDM6A可能结合在一起，从而影响XX动物的总脂肪。 建议的研究将阐明KDM5C和KDM6A影响性别差异的机制。 通过改变基因剂量的小鼠模型和培养的脂肪细胞研究肥胖和代谢 鉴定KDM5C和KDM6A基因组靶点。有三个具体目标：1.发现生理学 Kdm6a剂量在体内改变肥胖的机制。2.确定KDM5C和KDM6A基因组靶点 在白色脂肪组织中。3.确定Kdm5c和Kdm6a基因剂量对增重的贡献 在小鼠更年期模型中增加肥胖。拟议研究的完成将大大改善 我们对调节肥胖和肥胖性别差异的生理和分子机制的理解 代谢性疾病。 拟议的研究和培训计划将使我做好准备，成为一名独立调查员 研究重点是了解新陈代谢中驱动性别差异的遗传机制。 在REUE实验室接受的性别差异和脂肪组织生物学研究方面的培训将是对我之前的补充 在代谢性疾病和基因调控方面的研究经验，以实现我的职业目标。广博的 加州大学洛杉矶分校研究环境中可用的资源将进一步促进我的专业发展 加快我作为一名学术科学家的独立之路。重要的是，拟议的研究提供了一个 为我的独立研究奠定了基础，重点是Kdm6a，因为我正在过渡到独立。

PROJECT SUMMARY The physiological and functional properties of adipose tissue differ between females and males, which leads to differences in obesity and metabolic syndrome risk between the sexes. While the gonadal hormones contribute to these physiological sex differences, the Reue lab has demonstrated that the presence of XX or XY sex chromosomes further impacts adipose development and function in a sex-dependent manner. Specifically, the presence of two X chromosomes causes higher body weight and adiposity compared to XY animals. When two X chromosomes are present, genes on one X chromosome are inactivated to normalize gene expression to XY cells. However, a subset of these X chromosome genes escape inactivation resulting in higher expression in XX cells compared to XY cells. This leads to the hypothesis that higher X chromosome gene dosage impacts sex differences in adiposity. We identified two X chromosome genes, Kdm5c and Kdm6a, that impact adiposity in vivo by altering preadipocyte and mature adipocyte cellular function, respectively. Reduction of Kdm5c gene dosage in preadipocytes decreased body weight and adiposity, while reduced Kdm5c gene dosage in mature adipocytes had no impact on body weight or adiposity. Conversely, reduction of Kdm6a gene dosage in mature adipocytes reduced body weight and adiposity. Both Kdm5c and Kdm6a encode histone demethylase enzymes that modify chromatin structure to regulate gene expression across the genome. Thus, the combined actions of KDM5C in preadipocytes and KDM6A in mature adipocytes may coalesce to impact total adiposity in XX animals. The proposed studies will elucidate the mechanisms by which KDM5C and KDM6A influence sex differences in adiposity and metabolism through studies of mouse models with altered gene dosage, and in cultured adipocytes to identify KDM5C and KDM6A genomic targets. There are three Specific Aims: 1. Uncover physiological mechanisms by which Kdm6a dosage alters adiposity in vivo. 2. Identify KDM5C and KDM6A genomic targets in white adipose tissue. 3. Determine the contribution of Kdm5c and Kdm6a gene dosage to weight gain and increased adiposity in mouse menopause models. Completion of the proposed studies will significantly improve our understanding of physiological and molecular mechanisms that regulate sex differences in obesity and metabolic disease. The proposed research and training plan will prepare me to transition into an independent investigator position with a research emphasis on understanding genetic mechanisms driving sex differences in metabolism. The training in sex differences and adipose tissue biology research in the Reue lab will complement my prior research experience in metabolic disease and gene regulation to achieve my career goals. The extensive resources available within the UCLA research environment will further promote my professional development to accelerate my path to independence as an academic scientist. Importantly, the proposed research provides a foundation for my independent research, with an emphasis on Kdm6a, as I transition into independence.