Maternal obesity, AMPK and Developmental Programming

孕产妇肥胖、AMPK 和发育规划

• 批准号: 10535287
• 负责人: MIN DU
• 金额: $ 37.71万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-27 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10535287
• 关键词: 5' -AMP-activated protein kinase; Accounting; Adipocytes; Adult; Affect; American; Attenuated; Automobile Driving; Award; Body Weight; Brown Fat; Cell Lineage; Cells; Child; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Dermomyotome; Development; Diet; Elderly; Embryo; Embryonic Development; Enhancers; Fetal Development; Fetal Tissues; Fibroblasts; Genes; Glucose; Health; Homeobox; Impairment; Infiltration; Insulin Resistance; Knock-out; Knowledge; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Metformin; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Overweight; Pharmaceutical Preparations; Polycystic Ovary Syndrome; Predisposition; Pregnancy; Protein Kinase; Role; Sclerotome; Signal Transduction; Signaling Protein; Skeletal Muscle; Small Nuclear RNA; Somites; Source; Structure; Testing; Thinness; Tissues; Transcription Initiation Site; Woman; bone; bone morphogenic protein; dermatome; early onset; embryo tissue; fatty acid oxidation; fetal; fibrogenesis; improved; maternal obesity; molecular targeted therapies; mouse model; myogenesis; negative affect; obese mothers; obese person; offspring; offspring obesity; pregnant; prenatal; progenitor; programs; promoter; single-cell RNA sequencing; skeletal tissue; somitogenesis; stem cells; therapeutic development

Maternal obesity, AMPK and Developmental Programming Over 30% of pregnant American women are obese and an additional 30% are over-weight, conditions which negatively affect fetal development with long-term consequences for offspring health, including pre-disposition to obesity and type 2 diabetes (T2D). The underlying mechanisms remain poorly defined. Skeletal muscle (SM) accounts for >30% body weight and is a key tissue for the oxidation of fatty acids and glucose, as is brown adipose tissue (BAT). Under the support of our previous award, we demonstrated that maternal obesity (MO) elicits early onset of fibrotic and fatty infiltration (FFI) in offspring SM and BAT, which impairs their functions and programs metabolic disorders in offspring. We found that AMP-activated protein kinase (AMPK), a known target for metformin, is robustly inhibited due to MO, correlates with FFI and worsened offspring SM/BAT functions. In the early embryo, both myogenic and fibrogenic cells are derived from progenitor cells (PCs) in the dermomyotome. While the embryonic myogenic cells are the sources of both myogenic and brown adipogenic cells, embryonic fibrogenic cells are sources of fibrogenic and white adipogenic cells in offspring SM/BAT. Because of this, our previous studies point to embryonic origins for developmental abnormalities of offspring SM/BAT due to MO, but this is yet to be examined. Using single cell RNA sequencing (scRNA-seq), we found that embryonic myogenesis is attenuated in E9.5 MO embryos. We hypothesize that MO suppresses AMPK, which inhibits myogenic commitment and drives uncommitted PCs to fibrogenesis during embryonic development, programming FFI in offspring SM/BAT. Accordingly, we have three specific aims: 1) Study AMPK inhibition due to MO in impairing embryonic myogenic commitment; 2) Evaluate AMPK in linking MO to enhanced embryonic fibrogenesis; and 3) Analyze AMPK as a target for improving embryonic SM/BAT development of MO and the resulting offspring SM/BAT functions. We will use single cell “omics” for analyzing embryonic tissues, and embryoid body culture for mechanistic exploration. Knowledge obtained will identify molecular targets for therapeutics to improve embryonic SM/BAT development and subsequent metabolic health of MO offspring, helping the increasing populations of obese mothers to deliver healthy children.

母体肥胖、AMPK与发育程序 超过30%的美国孕妇肥胖，另外30%的孕妇超重， 对胎儿发育产生负面影响，对后代健康产生长期影响，包括易感性 肥胖症和2型糖尿病（T2 D）。基本的机制仍然不明确。骨骼肌（SM） 占体重的30%以上，是脂肪酸和葡萄糖氧化的关键组织，棕色也是如此。 脂肪组织（BAT）。在上一个奖项的支持下，我们证明了母亲肥胖（MO） 在SM和BAT后代中，纤维化和脂肪浸润（FFI）的早期发作可能会损害其功能 并在后代中编程代谢紊乱。我们发现AMP激活蛋白激酶（AMPK），一种已知的 二甲双胍的靶点，由于MO而受到强烈抑制，与FFI和后代SM/BAT恶化相关 功能协调发展的在早期胚胎中，肌原性细胞和纤维原性细胞都来源于胚胎中的祖细胞（PC）。 皮肌刀而胚胎肌源性细胞是肌源性和棕色细胞的来源， 成脂细胞、胚胎成纤维细胞是后代成纤维细胞和白色成脂细胞的来源 SM/BAT。正因为如此，我们以前的研究指出，胚胎起源的发育异常， 后代SM/BAT由于MO，但这还有待检查。使用单细胞RNA测序（scRNA-seq）， 我们发现在E9.5MO胚胎中胚胎肌发生减弱。我们假设MO抑制 AMPK抑制肌原性定型，并在胚胎发育期间驱动未定型的PC发生纤维化 开发，在后代SM/BAT中编程FFI。因此，我们有三个具体的目标：1）研究AMPK 由于MO在损害胚胎肌原性定型中的抑制作用; 2）评价AMPK将MO与 增强的胚胎纤维形成;和3）分析AMPK作为改善胚胎SM/BAT的靶点 MO和由此产生的后代SM/BAT功能的发展。我们将使用单细胞“组学”来分析 胚胎组织和胚状体培养用于机制探索。获得的知识将识别 用于改善胚胎SM/BAT发育和随后的代谢的治疗剂的分子靶标 MO后代的健康，帮助越来越多的肥胖母亲生下健康的孩子。