Epigenetic mechanisms underlying sex differences in obesity

肥胖性别差异背后的表观遗传机制

• 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
• 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

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.

项目摘要 脂肪组织的生理和功能特性在女性和男性之间不同， 导致肥胖和代谢综合征风险的性别差异。而性腺激素 导致这些生理性别差异，Reue实验室已经证明，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发育和功能。具体而言， 与XY动物相比，两条X染色体的存在导致更高的体重和肥胖。当 当存在两条X染色体时，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染色体基因的一个子集逃脱失活，导致在细胞中的较高表达。 XX细胞与XY细胞相比。这导致了一个假设，即较高的X染色体基因剂量会影响 肥胖的性别差异我们确定了两个X染色体基因，Kdm5c和Kdm6a， 在体内通过分别改变前脂肪细胞和成熟脂肪细胞的细胞功能。Kdm5c基因的减少 前脂肪细胞中的剂量降低体重和肥胖，而成熟脂肪细胞中的Kdm 5c基因剂量降低 脂肪细胞对体重或肥胖没有影响。相反，在成熟小鼠中Kdm6a基因剂量的减少， 脂肪细胞减少体重和肥胖。Kdm5c和Kdm6a都编码组蛋白脱甲基酶 修饰染色质结构以调节基因组中的基因表达。因此， 前脂肪细胞中的KDM5C和成熟脂肪细胞中的KDM6A可能合并影响XX动物的总肥胖。 这些研究将阐明KDM5C和KDM6A影响性别差异的机制。 通过研究改变基因剂量的小鼠模型和培养的脂肪细胞， 以鉴定KDM5C和KDM6A基因组靶标。具体目标有三个：1。揭示生理 Kdm6a剂量改变体内肥胖的机制。2.识别KDM5C和KDM6A基因组靶标 在白色脂肪组织中。3.确定Kdm 5c和Kdm 6a基因剂量对体重增加的贡献， 小鼠更年期模型中的肥胖增加。完成拟议的研究将大大改善 我们对调节肥胖症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准备过渡到一个独立的调查员 该职位的研究重点是了解推动新陈代谢性别差异的遗传机制。 在Reue实验室进行的性别差异和脂肪组织生物学研究方面的培训将补充我之前的研究。 代谢疾病和基因调控的研究经验，以实现我的职业目标。的广泛 加州大学洛杉矶分校的研究环境中可用的资源将进一步促进我的专业发展， 加速我作为学术科学家的独立之路。重要的是，拟议的研究提供了一个 这是我独立研究的基础，重点是Kdm6a，因为我过渡到独立。