Research Goals and Significance: Osteoporosis and obesity are major public health threats in the US. However, the underlying mechanisms, and whether these seemingly unrelated diseases have a common element, are unknown. During aging, bone mass decreases. At the same time, fat builds up in non-adipose tissues such as belly and bone marrow, suggesting that an imbalance may develop between the osteogenic and adipogenic differentiation pathways. PPAR(2, also known as the """"""""master"""""""" regulator of adipogenesis, positively regulates adipogenesis but has the opposite effect on osteogenesis. Our long-term goal is to determine the molecular mechanisms by which PPAR(2 controls both adipogenic and osteogenic pathways. The purpose of this research is to address the question of how PPAR(2 expression can be repressed by glucocorticoid-induced leucine zipper (GILZ), a recently identified leucine zipper protein. Since excess belly fat increases the risks of coronary disease and causes insulin resistance, both of which are major public health threats, understanding how PPAR(2 expression can be negatively regulated will provide solutions not only for treating osteoporosis, but obesity and obesity-related disorders as well. Rationale and Hypotheses: We and others have shown that the expression of PPAR(2 is activated by direct binding of the CCAAT/enhancer-binding proteins (C/EBPs) to the PPAR(2 promoter. In contrast, very little is known about how PPAR(2 can be negatively regulated. Our recent studies show that GILZ can suppress PPAR(2 transcription, inhibit adipogenic differentiation, and enhance osteogenic differentiation of bone marrow progenitor cells, the common precursors of fat- and bone-forming adipocytes and osteoblasts. Based on these studies and our recent preliminary data showing that GILZ interacts with the C/EBPs and inhibits C/EBP-mediated PPAR(2 expression, we hypothesize that GILZ represses PPAR(2 transcription by either inhibiting the binding of C/EBPs to the PPAR(2 promoter or by disrupting C/EBP transactivation functions via GILZ-C/EBP interactions. Based on recent evidence that 1) PPAR(2 inhibits Runx2/Cbfa1 expression and osteoblast differentiation;2) PPAR( agonists induce bone loss and marrow adiposity;and 3) PPAR( insufficiency enhances osteogenesis and increases bone formation, and protects mice against diet- induced obesity and insulin resistance, we also hypothesize that GILZ overexpression in vivo will reduce the level of PPAR(2 expression, thus reducing the susceptibility of mice to PPAR( agonist-induced bone loss and marrow adiposity, and protecting against high-fat diet-induced obesity and insulin resistance.
Specific Aims and Approaches:
Our Specific Aims are to test the above two hypotheses using state-of-the- art molecular biology approaches, including DNA-protein and protein-protein interactions, transcriptional activities, and knockdown approaches (Aim #1, in vitro studies), and to validate our hypothesis developed in Aim #1 using GILZ transgenic mice that have been recently generated in our laboratory (Aim #2, in vivo studies).

Public Health Relevance

Osteoporosis and obesity are major public health threats in the US. However, the underlying mechanisms, and whether these seemingly unrelated diseases have a common element, are unknown. During aging, bone mass decreases and fat builds up in belly and bone marrow, resulting in osteoporosis and the diseases that are associated with excess body fat, such as insulin resistance and coronary vascular diseases. Peroxisome proliferators-activated receptor-gamma2 (PPAR(2), also known as the """"""""master"""""""" regulator of adipogenesis, positively regulates adipocyte differentiation but has the opposite effect on osteoblast differentiation. Thus, understanding how PPAR(2 can be negatively regulated, a focus of this study, may lead to new therapies for treating osteoporosis and obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
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Margolis, Ronald N
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Georgia Regents University
Schools of Medicine
United States
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Yang, Nianlan; Baban, Babak; Isales, Carlos M et al. (2015) Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism. FASEB J 29:3954-63
Cao, Jay; Ou, Guomin; Yang, Nianlan et al. (2015) Impact of targeted PPAR? disruption on bone remodeling. Mol Cell Endocrinol 410:27-34
Pan, Guodong; Cao, Jay; Yang, Nianlan et al. (2014) Role of glucocorticoid-induced leucine zipper (GILZ) in bone acquisition. J Biol Chem 289:19373-82
He, Linlin; Yang, Nianlan; Isales, Carlos M et al. (2012) Glucocorticoid-induced leucine zipper (GILZ) antagonizes TNF-? inhibition of mesenchymal stem cell osteogenic differentiation. PLoS One 7:e31717