Maternal Obesity affects AMP-Kinase in Muscle Cell Differentiation

Summary

Principal 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

  1. pmc 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
  2. pmc 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
  3. pmc 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
  4. pmc 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
  5. pmc 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
  6. pmc 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
  7. pmc 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
  8. pmc 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
  9. pmc 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
  10. pmc 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

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
  3. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
  4. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
  5. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  7. Adiponectin, placental nutrient transport and fetal growth
    Theresa L Powell; Fiscal Year: 2013
  8. Mechanisms of Health Effects of Exercise in Children
    Dan M Cooper; Fiscal Year: 2013
  9. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  10. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013

Detail Information

Publications14

  1. pmc 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...
  2. pmc 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
    ....
  3. pmc 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
    ....
  4. pmc 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. ..
  5. pmc 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...
  6. pmc 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...
  7. pmc 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...
  8. pmc 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...
  9. pmc 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...
  10. pmc 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...
  11. pmc 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...
  12. pmc 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
    ....
  13. pmc 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
    ....
  14. pmc 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 Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE 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. ..
  2. Pathobiology of the Enteric System
    Joseph 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. ..
  3. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  4. Elafin Therapy for Lung Diseases
    Marlene 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. ..
  5. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  6. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  7. Adiponectin, placental nutrient transport and fetal growth
    Theresa L Powell; Fiscal Year: 2013
    ....
  8. Mechanisms of Health Effects of Exercise in Children
    Dan 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. ..
  9. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  10. Novel Mechanistic Targets of Steroid Hormones in the Brain
    Meharvan Singh; Fiscal Year: 2013
    ....
  11. Adiponectin and fetal programming
    Jianhua 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. ..
  12. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  13. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  14. Regulation of Maternal Fuel Supply and Neonatal Adiposity
    LINDA ANNE BARBOUR; Fiscal Year: 2013
    ....
  15. Molecular and Cellular Basis for Digestive Diseases
    Richard M Peek; Fiscal Year: 2013
    ..The Administrative Core also contains Biostatistics and Enrichment Programs and oversees the financial management and operation of the VDDRC. ..
  16. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry 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. ..
  17. Neurohumoral control of veins in hypertension
    Gregory 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. ..
  18. Cellular Senescence and Aging
    James 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. ..