Research Topics
Genomes and GenesSpecies | Maternal Obesity affects AMP-Kinase in Muscle Cell DifferentiationSummaryPrincipal Investigator: Min Du Abstract: DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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. Funding Period: 2010-09-27 - 2015-07-31 more information: NIH RePORT Top Publications
Research Grants
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Detail Information
Publications
Maternal obesity, inflammation, and fetal skeletal muscle development
Min Du
Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071, USA
Biol Reprod 82:4-12. 2010..More studies are needed to further explore the underlying mechanisms associated with maternal obesity, inflammation, and the commitment of MSCs...AMP-activated protein kinase mediates myogenin expression and myogenesis via histone deacetylase 5
Xing Fu
Department of Animal Sciences, Washington State University, Pullman, Washington
Am J Physiol Cell Physiol 305:C887-95. 2013....Maternal obesity induces epigenetic modifications to facilitate Zfp423 expression and enhance adipogenic differentiation in fetal mice
Qi Yuan Yang
Department of Animal Sciences, Washington State University, Pullman, Washington
Diabetes 62:3727-35. 2013....Emerging roles of zinc finger proteins in regulating adipogenesis
Shengjuan Wei
College of Animal Science and Technology, Northwest A and F University, Yangling, 712100, Shaanxi, People s Republic of China
Cell Mol Life Sci 70:4569-84. 2013..Taken together, these data lead to the conclusion that ZFPs may become promising targets to combat human obesity. ..Zfp423 promotes adipogenic differentiation of bovine stromal vascular cells
Yan Huang
Developmental Biology Group, Department of Animal Science, University of Wyoming, Laramie, WY, USA
PLoS ONE 7:e47496. 2012..In conclusion, data show that Zfp423 is a critical regulator of adipogenesis in stromal vascular cells of bovine muscle, and Zfp423 may provide a molecular target for enhancing intramuscular adipogenesis and marbling in beef cattle...AMP-activated protein kinase stimulates myostatin expression in C2C12 cells
Arun K Das
Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA
Biochem Biophys Res Commun 427:36-40. 2012..These results indicate that AMPK stimulates myostatin expression in C2C12 cells, providing an explanation for the negative effect of AMPK on muscle growth...Maternal obesity downregulates microRNA let-7g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development
X Yan
Department of Animal Science, University of Wyoming, Laramie, WY, USA
Int J Obes (Lond) 37:568-75. 2013..However, the mechanisms are poorly understood. MicroRNAs (miRNAs) regulate mRNA stability. We hypothesized that maternal obesity alters fetal muscle miRNA expression, thereby influencing intramuscular adipogenesis...Maternal obesity enhances collagen accumulation and cross-linking in skeletal muscle of ovine offspring
Yan Huang
Developmental Biology Group, Department of Animal Science, Center for the Study of Fetal Programming, University of Wyoming, Laramie, Wyoming, United States of America
PLoS ONE 7:e31691. 2012..Our observation that the collagen content and cross-linking are enhanced in MO offspring muscle is significant, because fibrosis is known to impair muscle functions and is a hallmark of muscle aging...AMP-activated protein kinase regulates beta-catenin transcription via histone deacetylase 5
Jun Xing Zhao
Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071, USA
J Biol Chem 286:16426-34. 2011..Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/β-catenin signaling pathway...Maternal obesity-impaired insulin signaling in sheep and induced lipid accumulation and fibrosis in skeletal muscle of offspring
Xu Yan
The Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, Wyoming, USA
Biol Reprod 85:172-8. 2011..These data clearly show that maternal obesity impairs the function of the skeletal muscle of offspring, supporting the fetal programming of adult metabolic diseases...Fetal muscle development, mesenchymal multipotent cell differentiation, and associated signaling pathways
M Du
Developmental Biology Group, Department of Animal Science, University of Wyoming, Laramie 82071, USA
J Anim Sci 89:583-90. 2011..Possible involvement of epigenetic modifications associated with histone deacetylases class IIa and histone acetyltransferase, p300, in MC differentiation is also discussed...AMP-activated protein kinase (AMPK) cross-talks with canonical Wnt signaling via phosphorylation of beta-catenin at Ser 552
Junxing Zhao
Developmental Biology Group, Department of Animal Science, College of Agriculture, University of Wyoming, Laramie, WY 82071, USA
Biochem Biophys Res Commun 395:146-51. 2010....Up-regulation of Toll-like receptor 4/nuclear factor-kappaB signaling is associated with enhanced adipogenesis and insulin resistance in fetal skeletal muscle of obese sheep at late gestation
Xu Yan
Department of Animal Science, Center for the Study of Fetal Programming, University of Wyoming, Laramie, Wyoming 82071, USA
Endocrinology 151:380-7. 2010....AMP-activated protein kinase α1 but not α2 catalytic subunit potentiates myogenin expression and myogenesis
Xing Fu
Department of Animal Sciences, Washington State University, Pullman, Washington, USA
Mol Cell Biol 33:4517-25. 2013..In summary, these results indicate that AMPK activity promotes myogenesis through a mechanism mediated by AMPKα1. ..
Research Grants
- The Center for Native and Pacific Health Disparities ResearchMARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
- Pathobiology of the Enteric SystemJoseph H Szurszewski; Fiscal Year: 2013..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
- Host Factors in Regulation of Inflammatory and Fibroproliferative Lung DiseasePAUL WESLEY NOBLE; Fiscal Year: 2013..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
- Elafin Therapy for Lung DiseasesMarlene Rabinovitch; Fiscal Year: 2013..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
- PPG - Mechanisms of Cardiovascular Protection and DiseaseDonald D Heistad; Fiscal Year: 2013..abstract_text> ..
- CARDIOVASCULAR DYNAMICS AND THEIR CONTROLJohn E Hall; Fiscal Year: 2013..End of Abstract) ..
- Adiponectin, placental nutrient transport and fetal growthTheresa L Powell; Fiscal Year: 2013....
- Mechanisms of Health Effects of Exercise in ChildrenDan M Cooper; Fiscal Year: 2013..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
- Mechanisms of Atherogenesis in Insulin ResistanceIRA A TABAS; Fiscal Year: 2013..End of Abstract) ..
- Novel Mechanistic Targets of Steroid Hormones in the BrainMeharvan Singh; Fiscal Year: 2013....
- Adiponectin and fetal programmingJianhua Shao; Fiscal Year: 2013..These studies will reveal new pathways of fetal programming that will lead to new therapeutic approaches to stop the vicious cycle of maternal-offspring obesity. ..
- MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATIONSalvatore DiMauro; Fiscal Year: 2013....
- Inflammatory responses of vascular cellsPaul L Fox; Fiscal Year: 2013..abstract_text> ..
- Regulation of Maternal Fuel Supply and Neonatal AdiposityLINDA ANNE BARBOUR; Fiscal Year: 2013....
- Molecular and Cellular Basis for Digestive DiseasesRichard M Peek; Fiscal Year: 2013..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
- Semi-volatile PCBs: Sources, Exposures, ToxicitiesLarry W Robertson; Fiscal Year: 2013..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
- Neurohumoral control of veins in hypertensionGregory D Fink; Fiscal Year: 2013..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
- Cellular Senescence and AgingJames L Kirkland; Fiscal Year: 2013..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..