Maternal obesity, AMPK and Developmental Programming

孕产妇肥胖、AMPK 和发育规划

• 批准号: 10672327
• 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/10672327
• 关键词: 5' -AMP-activated protein kinase; Accounting; Adipocytes; Adult; Affect; American; Attenuated; Automobile Driving; Award; Body Weight; Bone Morphogenetic Proteins; Brown Fat; Cell Lineage; Cells; Child; Coupled; Data; Dermomyotome; Development; Diet; Elderly; Embryo; Embryonic Development; Enhancers; Fetal Development; Fetal Skeleton; 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; Role; Sclerotome; Signal Transduction; Signaling Protein; Skeletal Muscle; Somites; Source; Structure; Testing; Thinness; Tissues; Transcription Initiation Site; Woman; bone; 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 nucleus RNA-sequencing; single-cell RNA sequencing; skeletal tissue; somitogenesis; stem cells; therapeutic development; 5' -AMP-activated protein kinase; Accounting; Adipocytes; Adult; Affect; American; Attenuated; Automobile Driving; Award; Body Weight; Bone Morphogenetic Proteins; Brown Fat; Cell Lineage; Cells; Child; Coupled; Data; Dermomyotome; Development; Diet; Elderly; Embryo; Embryonic Development; Enhancers; Fetal Development; Fetal Skeleton; 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; Role; Sclerotome; Signal Transduction; Signaling Protein; Skeletal Muscle; Somites; Source; Structure; Testing; Thinness; Tissues; Transcription Initiation Site; Woman; bone; 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 nucleus RNA-sequencing; 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.

孕产妇肥胖，AMPK和发育节目 超过30％的孕妇妇女肥胖，另外30％的疾病是 负面影响胎儿的发育，对后代健康的长期后果，包括前置前的影响 肥胖和2型糖尿病（T2D）。基本机制的定义仍然很差。骨骼肌（SM） 占体重> 30％的体重，是氧化脂肪酸和葡萄糖的关键组织，棕色也是 脂肪组织（蝙蝠）。在我们以前的奖项的支持下，我们证明了物物肥胖症（MO） 在后代SM和BAT中引起纤维化和脂肪浸润（FFI）的早期发作，这会损害其功能 和后代的代谢疾病。我们发现AMP激活的蛋白激酶（AMPK）是已知的 二甲双胍的靶标，由于MO而受到牢固抑制，与FFI相关并恶化后代SM/BAT 功能。在早期的胚胎中，肌原性和纤维基因均源自祖细胞（PC） 皮肤病组。胚胎肌原性细胞是肌原性和棕色的来源 掺杂细胞，胚胎纤维生成细胞是后代中纤维生成和白色掺杂细胞的来源 SM/蝙蝠。因此，我们以前的研究指出了胚胎起源于发育异常 由于mo而导致的后代SM/蝙蝠，但这尚待检查。使用单细胞RNA测序（SCRNA-SEQ）， 我们发现胚胎肌发生在E9.5 mo胚胎中减弱。我们假设MO抑制 AMPK，它抑制肌源性承诺并在胚胎期间驱动未承诺的PC进行纤维化 开发，后代SM/BAT的编程FFI。根据，我们有三个具体的目标：1）研究AMPK 由于MO引起的抑制作用会损害胚胎肌源性承诺； 2）评估将MO链接到与的AMPK 增强的胚胎纤维发生； 3）分析AMPK作为改善胚胎SM/BAT的目标 MO的开发以及由此产生的后代SM/BAT功能。我们将使用单个单元格进行分析 胚胎组织和用于机械探索的胚胎体培养。获得的知识将确定 用于改善胚胎SM/BAT发育和随后代谢的治疗的分子靶标 莫后代的健康，帮助肥胖母亲越来越多的人群分娩健康的孩子。