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

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与发育规划 超过30%的美国孕妇肥胖，另有30%的孕妇超重，这些情况 对胎儿发育有负面影响，并对后代健康产生长期影响，包括倾向于 肥胖和2型糖尿病(T2D)。潜在的机制仍然没有明确的定义。骨骼肌(SM) 占体重的30%，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)。在我们之前的奖项的支持下，我们证明了母体肥胖(MO) 在子代SM和BAT中引起早期纤维化和脂肪渗透(FFI)，从而损害它们的功能 并对后代的新陈代谢紊乱进行编程。我们发现AMP激活的蛋白激酶(AMPK)是一种已知的 二甲双胍的靶标，由于MO而被强烈抑制，与FFI相关，并使后代SM/BAT恶化 功能。在早期胚胎中，肌源性细胞和纤维性细胞都是由祖细胞(PC)分化而来的。 皮肌刀。而胚胎生肌细胞是生肌细胞和棕色细胞的来源 成脂细胞、胚胎成纤维细胞是子代成纤维细胞和白色成脂细胞的来源 SM/BAT。正因为如此，我们之前的研究指出发育异常的胚胎起源。 后代SM/BAT由于MO，但这还有待检验。使用单细胞RNA测序(scRNA-seq)， 我们发现，在E9.5MO胚胎中，胚胎肌肉发生减弱。我们假设MO抑制了 AMPK，它抑制肌源性承诺，并推动未承诺的PC在胚胎期间形成纤维化 在后代SM/BAT中开发、编程FFI。因此，我们有三个具体的目标：1)研究AMPK MO对胚胎肌源性承诺的抑制作用；2)评价AMPK在MO与 3)分析AMPK作为改良胚胎SM/BAT的靶点 MO的发展和由此产生的后代SM/BAT功能。我们将使用单细胞“组学”进行分析 用于机械探索的胚胎组织和类胚体培养。所获得的知识将确定 治疗改善胚胎SM/BAT发育和随后代谢的分子靶点 帮助肥胖母亲人数不断增加的母亲生下健康孩子。

项目成果

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.

• DOI: 10.1210/en.2015-1546
• 发表时间: 2016
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Naisi Li;Qiyuan Yang;R. G. Walker;T. Thompson;M. Du;B. D. Rodgers

Embryonic exposure to hyper glucocorticoids suppresses brown fat development and thermogenesis via REDD1.

• DOI: 10.1016/j.scib.2020.10.015
• 发表时间: 2021-03-15
• 期刊: Science bulletin
• 影响因子: 18.9
• 作者: Chen YT;Hu Y;Yang QY;Liu XD;Son JS;de Avila JM;Zhu MJ;Du M
• 通讯作者: Du M

Nutrigenomic regulation of adipose tissue development - role of retinoic acid: A review.

• DOI: 10.1016/j.meatsci.2016.04.003
• 发表时间: 2016-10
• 期刊: Meat science
• 影响因子: 7.1
• 作者: Wang B;Yang Q;Harris CL;Nelson ML;Busboom JR;Zhu MJ;Du M
• 通讯作者: Du M

Meat Science and Muscle Biology Symposium: extracellular matrix in skeletal muscle development and meat quality.

• DOI: 10.2527/jas.2011-4937
• 发表时间: 2012-03
• 期刊: Journal of animal science
• 影响因子: 3.3
• 作者: Du M;Carlin KM
• 通讯作者: Carlin KM