Effects of High Fat Diet and Environmental Obesogen Co-Exposure on Osteoporosis


Principal Investigator: Jennifer J Schlezinger
Abstract: DESCRIPTION (provided by applicant): Osteoporosis is the primary public health threat for the aging population. Osteoporosis has been likened to "obesity of the bone" because normal bone mass is lost as it is replaced with adipose tissue. A well recognized risk factor for development of osteoporosis is the decline of estrogen secretion in women at menopause. A newly recognized risk factor is a high fat diet and obesity. An underappreciated aspect of this bone health crisis is the contribution of exposure to environmental obesogens, contaminants that disrupt the homeostatic controls of adipogenesis and energy balance. A growing number of environmental contaminants, including organotins and phthalates, are being recognized for their ability to activate peroxisome proliferator activated receptor gamma (PPAR?), the master regulator of adipocyte differentiation. Activation of PPAR? in bone is associated with increased adipogenesis and decreased osteogenesis. Since PPAR? is poised at the apex of a regulatory network that controls multi-potent marrow stem cell (MSC) differentiation, it is posited that environmental obesogens are bone marrow toxicants. What is unclear is how exposure to both a high fat diet and environmental obesogens cooperate to modify bone homeostasis. The long term goal is to determine how activation of nuclear receptors in the bone marrow by environmental contaminants modifies MSC differentiation and how skewed MSC differentiation impacts bone marrow function. The objective of this proposal is to examine how exposure to a high fat diet and environmental obesogens cooperate to impair osteogenesis. It is hypothesized 1) that environmental obesogens induce adipogenesis and suppress osteogenesis through activation of PPAR? and RXR, which is a central point of regulatory control in directing MSC differentiation between osteogenic and adipogenic lineages, 2) that co-exposure to dietary fatty acids facilitates adipogenesis and 3) that exposure to a high fat diet will synergize with environmental obesogens to accelerate the progression of osteo- porosis in vivo. By pursuing the following two Specific Aims these hypotheses will be tested: 1) Determine the functional interactions of fatty acid and obesogen exposure and their effects on the mechanisms that control MSC differentiation. Alterations in central transcriptional mechanisms that control the balance between adipogenic and osteogenic differentiation that are induced by a phthalate, an organotin, and dietary fatty acids in primary MSC cultures and define the qualitative/quantitative effects of co-exposure will be delineated. 2) Examine the effect of a high fat diet on obesogen-induced osteoporosis in vivo. The effect of low dose tributyltin (TBT) exposure and diets differing in fat content in intact and ovariectomized female C57BL/6 mice on bone structure, quality and expression of mediators of adipogenesis, osteogenesis and osteoclast activity will be investigated. Given the growing aging population that is already at risk for development of osteoporosis, it is urgent that the molecular mechanisms driving diet- and contaminant-driven suppression of osteogenesis be identified so that appropriate approaches can be developed to prevent the onset/progression of disease.
Funding Period: 2012-09-01 - 2014-08-31
more information: NIH RePORT

Detail Information

Research Grants30

    Robert H Tukey; Fiscal Year: 2013
    ..Our combined efforts are anticipated to provide new insights into the molecular mechanisms that lead to environmental illness, and improve our understanding of the consequences of exposure to Superfund site contaminants. ..
  2. Mechanisms of Bone Loss from Administration of the Second-Generation Antipsychoti
    KATHERINE JEAN MOTYL; Fiscal Year: 2013
    ..My results will also add to the increasing evidence for a key role of the nervous system in regulating skeletal homeostasis. ..
    Bjorn Reino Olsen; Fiscal Year: 2013
  4. The Role of Podocalyxin in Osteoclast Activity and Bone Metabolism
    Megan M Weivoda; Fiscal Year: 2013
    ..Additionally, studying the role of sex steroids in the Vav/PODXLdel bone phenotype may elucidate mechanisms that contribute to postmenopausal and age-related bone loss. ..
  5. Economics of Health, Wealth, and Well-Being
    DAVID A WISE; Fiscal Year: 2013
    ..Subproject 8 explores ways of Improving Health and Health Care for Minority and Aging Populations. ..
  6. HIV and Adiposity in Women: Effects on Bone Metabolism
    Anjali Sharma; Fiscal Year: 2013
    ..The proposed study will allow the candidate to conduct high quality research in a timely and cost-effective manner, and examine the mechanism by which HIV-associated fat changes might affect bone loss in HIV-infected women. ..
  7. Alcohol-Induced Bone Resorption: The Role of Oxidative Stress
    Martin J J Ronis; Fiscal Year: 2013
    ..In addition, in vivo studies will be conducted to examine the ability of antioxidants to block EtOH-induced bone resorption. ..
  8. Interdisciplinary Study of Marrow Adiposity, Mineral Metabolism &Energy Balance
    CLIFFORD JAMES ROSEN; Fiscal Year: 2013
  9. Mechanisms by which LMP-1 Regulates Lineage Commitment in Mesenchymal Stem Cells
    FRANCES LOUISA TITUS; Fiscal Year: 2013
    ..abstract_text> ..
  10. Role of C/EBPbeta in mechanical regulation of MSC potential
    Maya Styner; Fiscal Year: 2013
  11. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  12. Role of mechanically activated Src/mTORC2 signaling on cytoskeletal adaptation
    William Roy Thompson; Fiscal Year: 2013
  13. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  14. Prevention of age-associated musculoskeletal loss by n-3 fatty acids
    Md Mizanur Rahman; Fiscal Year: 2013
    ..abstract_text> ..
  15. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  16. Mechanical Control of Mesenchymal Stem Cell Lineage Allocation
    JANET E RUBIN; Fiscal Year: 2013
    ..We will look at direct effects to prevent adipogenesis (inhibition of PPAR? expression) and indirect [unreadable]- catenin inhibition of PPAR? responses. ..
  17. 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. ..
  18. Osteoporosis treatment response assessed by micromechanical modeling of MRI data.
    Felix W Wehrli; Fiscal Year: 2013
    ..The successful completion of the project will provide new insight into the potential for image-based computational biomechanics for monitoring prophylactic intervention. ..
  19. Exploring The Posterior Pituitary-Bone Connection
    Mone Zaidi; Fiscal Year: 2013
    ..Our studies should help establish OT and Oxtrs as potential targets for treating human osteoporosis. ..
  20. Impact of Amyloid on the Aging Brain
    Reisa A Sperling; Fiscal Year: 2013
    ..This PPG brings together an exceptional multidisciplinary team of clinical, statistical, cognitive neuroscience, imaging, and laboratory investigators dedicated to exploring the impact of amyloid on the aging brain. ..
  21. Mechanistic basis of probiotic prevention of osteoporosis
    Narayanan Parameswaran; Fiscal Year: 2013
    ..Our findings will also provide the foundation for future clinical studies to determine the effectiveness of probiotics to maximize bone health in post-menopausal women. ..