Paternal Contributions to Metabolic Disease in Offspring: Environment, Epigenetics, and Sperm

父亲对后代代谢疾病的影响：环境、表观遗传学和精子

• 批准号: 10480820
• 负责人: Mary E Patti
• 金额: $ 74.1万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10480820
• 关键词: Adult; Adult Children; Affect; Age; Bile Acids; Binding Sites; Body Weight; Breeding; Caloric Restriction; Cell Cycle Regulation; Cell Nucleus; Cell Respiration; Cells; Conceptions; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Educational Intervention; Elements; Embryo; Enhancers; Environment; Epigenetic Process; Exposure to; Fasting; Fathers; Fatty Liver; Fertilization in Vitro; Funding; Future Generations; Gene Expression; Generations; Genes; Genetic; Genetic Transcription; Germ Cells; Glucose; Glucose Intolerance; Health; Human; Hyperglycemia; Injections; Insulin Resistance; Interruption; Intervention; Knockout Mice; Life; Link; Lipids; Liver; Malnutrition; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Mothers; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Parents; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Placenta; Placentation; Population; Pregnancy; Public Health; Regulator Genes; Resistance; Risk; Small RNA; Somatic Cell; Testing; Therapeutic Intervention; Tissues; Umbilical Cord Blood; Weight Gain; Work; adenylate kinase; bisulfite sequencing; blastocyst; burden of illness; cdc Genes; dietary; differential expression; disorder risk; embryo tissue; epigenetic regulation; epigenome; exercise training; fetal; improved; in vivo; inhibitor; innovation; intergenerational; lipid metabolism; male; metabolic phenotype; molecular phenotype; mouse model; non-genetic; novel strategies; offspring; programs; promoter; response; sperm cell; transcription factor; transcriptome; transcriptome sequencing; transcriptomics; transmission process

PROJECT SUMMARY One novel approach to reduce the burden of type 2 diabetes and obesity comes from the recognition that parental obesity or diabetes can increase risk of metabolic disease in offspring via non-genetic effects. This perspective raises the exciting possibility that treatment of parents to improve their metabolism before conception could interrupt vicious intergenerational cycles of obesity and diabetes, thus improving offspring health. In the prior funding cycle, we developed evidence for the impact of paternally-focused interventions on the sperm epigenome and offspring health. We recently demonstrated in humans that paternal obesity is associated with altered DNA methylation in cord blood of offspring7. Our new data in mice indicate (1) paternal obesity and hyperglycemia are key determinants of offspring health, (2) improving paternal metabolism - by treatment with either SGLT2 inhibitors or caloric restriction - can reverse age-associated weight gain, insulin resistance, glucose intolerance, and fatty liver in F1 offspring, (3) paternal metabolism potently modifies the transcriptome in fetal and adult offspring, including oxidative and lipid regulatory genes, and (4) paternal metabolism alters the epigenome in both sperm and offspring tissue. For example, DNA hydroxymethylation (5hmC) at enhancers adjacent to differentially expressed genes is reduced in sperm of HFD-fed males, and reciprocally increased in males treated with SGLT2i or the AMP kinase activator AICAR. In this revised application, we will utilize this innovative mouse model to identify the mechanisms by which paternal health and its treatment modulate the paternal germ cell epigenome to improve offspring health, and to test the hypothesis that the AMPK-Tet2 pathway, a mediator of glucose-mediated epigenetic regulation, mediates observed differences in sperm 5hmC and offspring metabolic disease. In Aim 1, we will define the impact of paternal obesity and hyperglycemia, and its reversal, on the germ cell epigenome (5mC/5hmC, small RNA), and identify key cis-regulating elements. In Aim 2, we will determine the pathogenicity of germ cell epigenetic changes by evaluating offspring outcomes after in vitro fertilization and sperm-derived ncRNA injection. Aim 3 will determine whether paternal effects on offspring are mediated via direct effects on the embryo, or on extraembryonic lineages affecting placental development, using single-cell transcriptomic analysis of blastocysts at a single-cell level and detailed morphometric analysis of placentae derived from control, HFD, and HFD+CANA-treated fathers. Aim 4 will test the hypothesis that the AMPK-Tet2 pathway, a mediator of glucose- mediated epigenetic regulation in somatic cells, also mediates glucose-induced changes in the germ cell epigenome. We will analyze the impact of AMPK activation in vivo on 5hmC in sperm from wild type or Tet2-null mice and on offspring phenotypes. In summary, identification of causal mechanisms in response to paternal hyperglycemia and obesity - and its reversal - will provide critical new information to guide development of new paternally-focused translatable approaches to reduce disease burden in future generations.

项目总结 减轻2型糖尿病和肥胖症负担的一种新方法来自于认识到父母 肥胖或糖尿病会通过非遗传效应增加后代患代谢性疾病的风险。这一视角 提出了一种令人兴奋的可能性，即在受孕前对父母进行治疗以改善他们的新陈代谢 中断肥胖和糖尿病的恶性代际循环，从而改善后代健康。 在之前的资助周期中，我们提出了父系干预对精子的影响的证据。 表观基因组与后代健康。我们最近在人类身上证明，父亲的肥胖与 子代脐带血DNA甲基化改变7。我们在老鼠身上的新数据表明：(1)父亲肥胖和 高血糖是后代健康的关键决定因素，(2)改善父亲的新陈代谢-通过治疗 SGLT2抑制剂或热量限制-可以逆转与年龄相关的体重增加、胰岛素抵抗、血糖 不耐受，以及F1后代的脂肪肝，(3)父亲的代谢有效地改变了胎儿的转录组 和成年后代，包括氧化和脂肪调节基因，以及(4)父亲的新陈代谢改变 精子和后代组织中的表观基因组。例如，DNA在增强剂上的羟甲基化(5hmC) 与差异表达基因相邻的基因在喂食HFD的雄性精子中减少，而在 接受SGLT2i或AMP激酶激活剂AICAR治疗的男性。 在这一修订的应用程序中，我们将利用这一创新的鼠标模型来确定 父系健康及其治疗调节父系生殖细胞表观基因组以改善后代健康，并 测试AMPK-TET2通路的假设，AMPK-TET2通路是葡萄糖介导的表观遗传调节的中介， 调节观察到的精子5hmC和后代代谢性疾病的差异。在目标1中，我们将定义 父亲肥胖和高血糖及其逆转对生殖细胞表观基因组(5mC/5hmC，Small)的影响 RNA)，并确定关键的顺式调节元件。在目标2中，我们将确定生殖细胞的致病性。 通过评估体外受精和精子来源的ncRNA后的后代结局来评价表观遗传学的变化 注射。目标3将确定父性对后代的影响是否通过对胚胎的直接影响来传递， 或影响胎盘发育的胚外血统，使用单细胞转录分析 单细胞水平的胚泡和来自对照、HFD和 HFD+CANA治疗的父亲。目的4将测试假设AMPK-TET2途径，一个葡萄糖的中介- 体细胞中介导的表观遗传调节，也介导了葡萄糖诱导的生殖细胞变化 表观基因组。我们将分析体内AMPK激活对野生型和TET2缺失型精子5hmC的影响 小鼠和后代的表型。综上所述，确定父性反应的因果机制 高血糖和肥胖--及其逆转--将提供关键的新信息来指导新的 以家长为中心的可翻译方法，以减少子孙后代的疾病负担。