Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma

Summary

Principal Investigator: Yihong Wan
Abstract: DESCRIPTION (provided by applicant): Bone is a dynamic tissue that constantly remodels by balancing osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The disruption of this tissue homeostasis causes several devastating human diseases including osteoporosis, arthritis and bone metastasis of cancers, leading to severe pain, fractures, life-threatening hypercalcemia, limited mobility and increased mortality. The nuclear receptor PPAR3 (peroxisome proliferator-activated receptor-3) is a critical regulator of energy metabolism and an important therapeutic target for treating the escalating obesity and diabetes epidemic. Emerging evidence suggests that PPAR3 also modulates bone turnover. We discovered that activation of PPAR3 promotes osteoclast differentiation and bone resorption. It has also been shown to suppress osteoblast differentiation and bone formation. Importantly, these findings unravel a central role for PPAR3 in the connection between mineral and energy metabolism, linking skeletal disorders such as osteoporosis with metabolic syndrome hallmarked by obesity, diabetes and atherosclerosis. Synthetic PPAR3 ligands thiazolidinediones (TZDs) are FDA-approved drugs for insulin resistance and type 2 diabetes. Recent clinical trials have reported that long-term use of TZDs increased fracture rates among diabetic patients. Thus, it is of paramount importance to understand how PPAR3 regulates bone metabolism. In this proposal, we hypothesize that 1) PPAR3 exerts a biphasic regulation of osteoclastogenesis, at both the early stage of osteoclast lineage commitment and the late stage of osteoclast differentiation;2) this regulation is influenced by the metabolic context and represents a critical mechanism for TZD-mediated bone loss. In Aim 1, we will determine the cellular mechanisms for osteoclast development by identifying its hematopoietic origin. In Aim 2, we will determine the molecular mechanisms for osteoclast lineage commitment and PPAR3 regulation. In Aim 3, we will determine how TZDs induce bone loss in the context of diabetes. A combination of tools will be employed, including mouse genetic and disease models, molecular and cell biology, biochemistry and small molecules. The proposed investigation will elucidate how PPAR3 regulates mineral metabolism by controlling osteoclast lineage commitment, differentiation and function, as well as how this regulation is influenced by energy metabolism. It will open exciting new paths to the understanding of skeletal physiology and its connection with metabolic diseases. Importantly, the outcome of these studies will provide fundamental insights for the treatment of diabetes, as well as other diseases associated with increased bone resorption such as osteoporosis, arthritis and cancer metastasis. Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community.
Funding Period: 2011-05-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4706-19. 2011
  2. pmc Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4692-705. 2011
  3. pmc Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:3143-8. 2012
  4. pmc Maternal western diet causes inflammatory milk and TLR2/4-dependent neonatal toxicity
    Yang Du
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Genes Dev 26:1306-11. 2012
  5. pmc Macrophage VLDL receptor promotes PAFAH secretion in mother's milk and suppresses systemic inflammation in nursing neonates
    Yang Du
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Nat Commun 3:1008. 2012
  6. pmc HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch
    Zixue Jin
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Mol Endocrinol 27:325-35. 2013
  7. pmc Bone marrow mesenchymal stem cells: fat on and blast off by FGF21
    Yihong Wan
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Int J Biochem Cell Biol 45:546-9. 2013
  8. pmc Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cell Metab 19:927-40. 2014

Research Grants

Detail Information

Publications9

  1. pmc Biphasic and dosage-dependent regulation of osteoclastogenesis by β-catenin
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4706-19. 2011
    ..Importantly, these findings suggest that Wnt activation is a more effective treatment for skeletal fragility than previously recognized that confers dual anabolic and anti-catabolic benefits...
  2. pmc Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9041, USA
    Mol Cell Biol 31:4692-705. 2011
    ..These findings not only identify the long-sought-after osteoclast progenitors but also establish unprecedented tools for their visualization, isolation, characterization, and genetic manipulation...
  3. pmc Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 109:3143-8. 2012
    ..Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration...
  4. pmc Maternal western diet causes inflammatory milk and TLR2/4-dependent neonatal toxicity
    Yang Du
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Genes Dev 26:1306-11. 2012
    ..These findings unravel maternal western diet-induced inflammatory milk secretion as a novel aspect of the metabolic syndrome at the maternal offspring interface...
  5. pmc Macrophage VLDL receptor promotes PAFAH secretion in mother's milk and suppresses systemic inflammation in nursing neonates
    Yang Du
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Nat Commun 3:1008. 2012
    ....
  6. pmc HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch
    Zixue Jin
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
    Mol Endocrinol 27:325-35. 2013
    ..003) owing to 102% elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration...
  7. pmc Bone marrow mesenchymal stem cells: fat on and blast off by FGF21
    Yihong Wan
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Int J Biochem Cell Biol 45:546-9. 2013
    ..These new findings will further elucidate the dynamic regulation of BMMSCs in the pathophysiological control of skeletal homeostasis, and facilitate the clinical applications of BMMSCs in regenerative medicine...
  8. pmc Orexin regulates bone remodeling via a dominant positive central action and a subordinate negative peripheral action
    Wei Wei
    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Cell Metab 19:927-40. 2014
    ..These findings reveal orexin as a critical rheostat of skeletal homeostasis that exerts a yin-yang dual regulation and highlight orexin as a therapeutic target for osteoporosis. ..

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. Signal Transduction Mechanism of Osteoclast Differentiation
    Nandini Ghosh-Choudhury; Fiscal Year: 2013
    ..Our results will demonstrate how BMP-2 can orchestrate a complex transcriptional network in osteoblasts to tightly regulate osteoclast activation. ..
  3. DAP12 and ITAM-signals in Osteoclastogenesis
    Mary C Nakamura; Fiscal Year: 2013
    ..3. Determine the requirement for ROS during rapid osteoclastogenesis in the absence of ITAM- adapter signals. ..
  4. Transcriptional role of TLE3 in brown adipose tissue development and metabolism
    Claudio J Villanueva; Fiscal Year: 2013
    ..The proposed studies are a logical transition from my postdoctoral studies in adipogenesis to the burgeoning field of brown adipocyte biology. ..
  5. Pharmacology of Risperidone Effects on Bone Remodeling and Energy Metabolism
    Karen L Houseknecht; Fiscal Year: 2013
    ....
  6. Thrombopoietin: A novel regulator of bone healing
    Melissa A Kacena; Fiscal Year: 2013
    ..Understanding these mechanisms may provide insight into alternative treatment strategies for bone healing as well as systemic bone loss such as that seen in osteoporosis. ..
  7. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  8. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..