SIGNIFICANCE: 18-35% of pregnant American women are clinically obese, a condition which affects 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. RATIONALE: Skeletal muscle (SM) is a key tissue responsive to the oxidation of fatty acids and glucose, and its transition to insulin resistance (IR) precedes the onset of T2D. The fetal stage is crucial for SM development since there is no net increase in the number of SM fibers after birth. Our preliminary studies in fetal SM indicate that maternal obesity (MO) reduced AMP-activated protein kinase (AMPK) activity, and altered fetal SM development by enhancing intramuscular adipogenesis and fibrogenesis, both of which impair SM functions. Myocytes, adipocytes and fibroblasts in fetal SM are derived from mesenchymal stem cells (MSC). Our preliminary studies show that AMPK phosphorylates and enhances 2-catenin mediated signaling, a pathway promoting myogenesis. AMPK also phosphorylates p300, which is expected to impair its function as a co-activator, and p300 is a necessary co-activator for transcription factors regulating adipogenesis and fibrogenesis. AMPK catalytic subunit has two isoforms demonstrating slightly different roles in metabolism. CENTRAL HYPOTHESIS: MO inhibits AMPK, which reduces phosphorylation of 2-catenin and p300 by AMPK, leads to the down-regulation of 2-catenin but enhancement of p300 mediated signaling and a shift from myogenesis to adipogenesis/fibrogenesis during fetal SM development. We have three SPECIFIC AIMS: 1) Evaluate whether 2-catenin is the key mediator linking AMPK to myogenesis in fetal SM;2) Examine the link between p300 phosphorylation by AMPK and adipogenesis/fibrogenesis in fetal SM;3) Assess the isoform specific effect of AMPK on myogenesis, adipogenesis and fibrogenesis. APPROACH: We plan to use mouse mesenchymal C3H10T1/2 cells to assess whether p300 and 2-catenin are key mediators between AMPK and MSC differentiation in fetal SM. We will also use the well-established diet-induced obesity mouse model to induce MO and the available AMPK-isoform-specific knockout mice to evaluate the role of AMPK in fetal SM development. Important mediators of selected signaling pathways will be analyzed at both mRNA and protein levels, as well as their location by immunohistochemical staining in fetal SM. OBJECTIVE: The objective is to test the role of AMPK in fetal SM development due to MO and to further explore mechanisms. INNOVATION: We are pioneering studies to define the role of AMPK in fetal SM development. The proposed work is novel, because the effects of AMPK and its associated signaling pathways on fetal SM development due to MO are just becoming to be appreciated. ENVIRONMENT: All methodologies required are already established in our laboratory. The Developmental Biology Group and the Center for the Study of Fetal Programming provide excellent academic environment, and animal and laboratory facilities. IMPACT: Proposed studies will demonstrate AMPK as a key mediator of fetal SM development, which will make it possible to use numerous available anti- diabetic drugs, known activators of AMPK, to prevent impairment of fetal SM development due to MO. Data and knowledge obtained will also allow us to further explore mechanisms regulating fetal SM development due to other maternal physiological stresses. Given the importance of SM for lifelong activities and its close association with obesity and T2D, such intervention will help the increasing number of obese pregnant women in this country to deliver healthy children.
The United States is experiencing an obesity epidemic which increasingly involves women of child bearing years. 18-35% of pregnant American women are clinically obese, a condition which affects fetal development with long-term consequences for offspring health, including pre-disposition to obesity and Type 2 diabetes. The underlying mechanisms are poorly defined. The objectives of proposed studies are to explore mechanisms associated with impairment of fetal skeletal muscle development due to maternal obesity. Knowledge obtained will allow us to further explore fetal skeletal muscle development due to maternal obesity and other maternal physiological stresses. Molecular mediators identified are targets for interventions to ensure proper skeletal muscle development in fetuses of obese women. Due to the importance of skeletal muscle for lifelong activities and its close association with obesity and Type 2 diabetes, such intervention will help the increasing number of obese pregnant women in this country to deliver healthy children.
|Wang, Songbo; Liang, Xingwei; Yang, Qiyuan et al. (2017) Resveratrol enhances brown adipocyte formation and function by activating AMP-activated protein kinase (AMPK) ?1 in mice fed high-fat diet. Mol Nutr Food Res 61:|
|Wang, Bo; Zhang, Faya; Zhang, Hui et al. (2017) Alcohol intake aggravates adipose browning and muscle atrophy in cancer-associated cachexia. Oncotarget 8:100411-100420|
|Wang, Bo; Fu, Xing; Liang, Xingwei et al. (2017) Maternal Retinoids Increase PDGFR?+ Progenitor Population and Beige Adipogenesis in Progeny by Stimulating Vascular Development. EBioMedicine 18:288-299|
|Griner, John D; Rogers, Carl J; Zhu, Mei-Jun et al. (2017) Lysyl oxidase propeptide promotes adipogenesis through inhibition of FGF-2 signaling. Adipocyte 6:12-19|
|Zhao, Junxing; Yang, Qiyuan; Zhang, Lupei et al. (2017) AMPK?1 deficiency suppresses brown adipogenesis in favor of fibrogenesis during brown adipose tissue development. Biochem Biophys Res Commun 491:508-514|
|Liang, Xingwei; Yang, Qiyuan; Fu, Xing et al. (2016) Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice. J Physiol 594:4453-66|
|Liang, Xingwei; Yang, Qiyuan; Zhang, Lupei et al. (2016) Maternal high-fat diet during lactation impairs thermogenic function of brown adipose tissue in offspring mice. Sci Rep 6:34345|
|Yang, Qiyuan; Liang, Xingwei; Sun, Xiaofei et al. (2016) AMPK/?-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis. Cell Metab 24:542-554|
|Wei, Shengjuan; Du, Min; Jiang, Zhihua et al. (2016) Long noncoding RNAs in regulating adipogenesis: new RNAs shed lights on obesity. Cell Mol Life Sci 73:2079-87|
|Miao, Z G; Zhang, L P; Fu, X et al. (2016) Invited review: mesenchymal progenitor cells in intramuscular connective tissue development. Animal 10:75-81|
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