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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要减轻2型糖尿病和肥胖负担的一种新颖方法来自于父母的认识肥胖或糖尿病可以通过非遗传作用增加后代代谢疾病的风险。这个观点增加了令人兴奋的可能性，即在受孕之前，对父母的治疗改善新陈代谢中断肥胖和糖尿病的恶性代际周期，从而改善了后代的健康。在先前的融资周期中，我们为陪伴以父母为中心的干预措施的影响开发了证据表观基因组和后代健康。我们最近在人类中证明父亲肥胖与后代血液中的DNA甲基化改变了DNA甲基7。我们在小鼠中的新数据表明（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，葡萄糖 F1后代中的不耐受和脂肪肝，（3）父亲代谢有效地改变了胎儿的转录组和成人后代，包括氧化和脂质调节基因，（4）父亲代谢改变了精子和后代组织的表观基因组。例如，在增强剂处的DNA羟甲基（5HMC）在HFD喂养的雄性精子中，与差异表达的基因相邻，并相互增加用SGLT2I或AMP激酶活化剂AICAR处理的雄性。在此修订的应用程序中，我们将利用此创新的鼠标模型来确定该机制父亲健康及其治疗调节父亲的生殖细胞表观基因组，以改善后代健康，并检验以下假设：AMPK-TET2途径是葡萄糖介导的表观遗传学调节的介体介导精子5HMC和后代代谢疾病的观察到差异。在AIM 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的影响（5MC/5HMC，小 RNA），并确定关键的顺式调节元件。在AIM 2中，我们将确定生殖细胞的致病性体外受精后的后代结果和精子衍生的NCRNA，表观遗传变化注射。 AIM 3将确定父亲对后代的影响是否是通过直接对胚胎的影响介导的，或使用影响胎盘发育的外囊外谱系，使用单细胞转录组分析单细胞水平的胚泡和对照，HFD和 HFD+CANA处理的父亲。 AIM 4将检验以下假设：AMPK-TET2途径是葡萄糖的介体体细胞中介导的表观遗传调节，还介导葡萄糖诱导的生殖细胞变化表观基因组。我们将分析野生型或TET2-NULL的AMPK激活在体内对精子中5HMC的影响小鼠和后代表型。总之，响应父亲的因果机制的鉴定高血糖和肥胖 - 及其逆转 - 将提供关键的新信息，以指导新的新信息以亲子量为中心的翻译方法减轻后代的疾病负担。