Maternal obesity, AMPK and Developmental Programming

孕产妇肥胖、AMPK 和发育规划

基本信息

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
项目类别：
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&apos -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

项目摘要

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 和发育规划超过 30% 的美国孕妇肥胖，另有 30% 超重，这些情况对胎儿发育产生负面影响，对后代健康产生长期影响，包括预先倾向肥胖和 2 型糖尿病 (T2D) 的潜在机制仍不清楚。占体重的 30% 以上，与棕色组织一样，是氧化脂肪酸和葡萄糖的关键组织在我们之前的奖项的支持下，我们证明了孕产妇肥胖（MO）。引起后代 SM 和 BAT 早期出现纤维化和脂肪浸润 (FFI)，从而损害其功能我们发现 AMP 激活蛋白激酶 (AMPK)，一种已知的代谢紊乱。二甲双胍的目标，由于 MO 而受到强烈抑制，与 FFI 和后代 SM/BAT 恶化相关在早期胚胎中，肌原细胞和纤维原细胞均源自祖细胞（PC）。而胚胎肌原细胞是肌原细胞和棕色细胞的来源。脂肪形成细胞、胚胎纤维形成细胞是后代纤维形成和白色脂肪形成细胞的来源因此，我们之前的研究指出发育异常的胚胎起源。 MO 导致后代 SM/BAT，但这还有待使用单细胞 RNA 测序 (scRNA-seq) 进行检查，我们发现 E9.5 MO 胚胎中胚胎肌发生减弱。 AMPK，在胚胎期间抑制肌源性定向并驱动未定向的 PC 纤维化因此，我们有三个具体目标： 1）研究 AMPK。 MO 对胚胎肌源性承诺的抑制；2) 评估 AMPK 将 MO 与 3) 分析 AMPK 作为改善胚胎 SM/BAT 的靶点 MO 的发育以及由此产生的后代 SM/BAT 功能我们将使用单细胞“组学”进行分析。胚胎组织和胚状体培养用于机械探索所获得的知识将被识别。改善胚胎 SM/BAT 发育和随后代谢的治疗分子靶点 MO 后代的健康，帮助越来越多的肥胖母亲生育健康的孩子。

项目成果

期刊论文数量（59）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis.

DOI：
10.1016/j.cmet.2016.08.010
发表时间：
2016-10-11
期刊：
Cell metabolism
影响因子：
29
作者：
Yang Q;Liang X;Sun X;Zhang L;Fu X;Rogers CJ;Berim A;Zhang S;Wang S;Wang B;Foretz M;Viollet B;Gang DR;Rodgers BD;Zhu MJ;Du M
通讯作者：
Du M

Myostatin Attenuation In Vivo Reduces Adiposity, but Activates Adipogenesis.