Epigenetic mechanisms underlying sex differences in obesity

肥胖性别差异背后的表观遗传机制

基本信息

批准号：
10606954
负责人：
Carrie Beth Wiese
金额：
$ 7.63万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606954
关键词：
ATAC-seq Acceleration Adipocytes Adipose tissue Alleles Animals Automobile Driving Biology Blood Vessels Body Weight Body Weight decreased Body fat Calorimetry Cell physiology Cells ChIP-seq Chemicals Chromatin Structure Complement Development Eating Environment Enzymes Epigenetic Process Fatty acid glycerol esters Female Foundations Gene Deletion Gene Dosage Gene Expression Gene Expression Regulation Genes Genetic Genome Genomics Goals Gonadal Hormones Histones Hormonal Hormones Human In Vitro Laboratories Lipids Lipolysis Liver Lysine Menopause Metabolic Metabolic Diseases Metabolic syndrome Metabolism Mitochondria Modeling Molecular Mus Obesity Ovarian hormone Ovariectomy Physiological Physiology Ploidies Positioning Attribute Postmenopause Prevalence Proliferating Property Research Research Personnel Resources Risk Role Scientist Sex Chromosomes Sex Differences Skeletal Muscle Tissues Training Weight Gain Woman X Chromosome X Inactivation adipocyte biology adiponectin blood glucose regulation career disorder risk dosage energy balance experience histone demethylase histone methylation improved in vivo lipid biosynthesis male men mouse model ovarian failure sex single-cell RNA sequencing

项目摘要

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.

项目概要女性和男性脂肪组织的生理和功能特性不同，这导致性别之间肥胖和代谢综合征风险的差异。虽然性腺激素导致这些生理性别差异的原因是，Reue 实验室已证明 XX 或 XY 的存在性染色体以性别依赖性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 染色体基因的一个子集逃脱了失活，导致在 XX 细胞与 XY 细胞相比。这导致了这样的假设：较高的 X 染色体基因剂量会影响肥胖的性别差异。我们确定了两个影响肥胖的 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 基因减少前脂肪细胞中的剂量降低了体重和肥胖，同时降低了成熟细胞中 Kdm5c 基因的剂量脂肪细胞对体重或肥胖没有影响。相反，成熟细胞中 Kdm6a 基因剂量的减少脂肪细胞减少体重和肥胖。 Kdm5c 和 Kdm6a 均编码组蛋白去甲基酶改变染色质结构以调节整个基因组的基因表达。因此，联合行动前脂肪细胞中的 KDM5C 和成熟脂肪细胞中的 KDM6A 可能联合影响 XX 动物的总肥胖。拟议的研究将阐明 KDM5C 和 KDM6A 影响性别差异的机制通过基因剂量改变的小鼠模型和培养脂肪细胞的研究来研究肥胖和代谢鉴定 KDM5C 和 KDM6A 基因组靶标。具体目标有三个： 1. 揭示生理学 Kdm6a 剂量改变体内肥胖的机制。 2. 识别 KDM5C 和 KDM6A 基因组靶标存在于白色脂肪组织中。 3.确定Kdm5c和Kdm6a基因剂量对体重增加的贡献和小鼠更年期模型的肥胖增加。完成拟议的研究将显着改善我们对调节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过渡为独立调查员的准备其研究重点是了解驱动新陈代谢性别差异的遗传机制。 Reue 实验室的性别差异和脂肪组织生物学研究培训将补充我之前的经验在代谢疾病和基因调控方面的研究经验，以实现我的职业目标。广泛的加州大学洛杉矶分校研究环境中的可用资源将进一步促进我的专业发展加速我作为一名学术科学家的独立之路。重要的是，拟议的研究提供了当我过渡到独立时，为我的独立研究奠定了基础，重点是 Kdm6a。