Date of Award

12-2007

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Advisor

Clifford J. Rosen

Second Committee Member

Mary L. Bouxsein

Third Committee Member

Beverly J. Paigen

Abstract

The central hypothesis of this thesis is that the activity of Peroxisome Proliferator Activated Receptor Gamma (PPARG) in bone is determined by both activating ligands and allelic differences. The B6.C3H-6T (6T) congenic strain was created to study the biology underlying a Quantitative Trait Locus (QTL) for Bone Mineral Density (BMD) and carries C3H/HeJ alleles for a region of Chromosome 6 on an otherwise C57BL/6JBm (B6) background. Using block haplotyping and gene expression analysis, it was concluded that Pparg was a candidate gene for this QTL. Activating PPARG by high fat feeding resulted in decreased bone mass in 6T but not in B6 mice. This PPARG allele by diet interaction for BMD was confirmed in humans. Unlike the B6 strain, the 6T strain was found to be resistant to diet induced obesity and high-fat-diet induced fatty liver. Gene expression analysis in the liver comparing high and low fat fed B6 and 6T mice demonstrated that the expression of Carbon Catabolite Repression 4-Like (Ccrn4l) was contingent on both the strain examined and the diet fed to the mice. The Ccrn4l-/- mice had previously been shown to exhibit altered diurnal patterns of Pparg expression and in this study, Ccrn4l expression was found to be coincident with adipocyte differentiation. The Ccrn4l-/- mice also demonstrated increased trabecular bone mass and decreased marrow adipocytes. Thus, CCRN4L, a deadenylase, and may contribute to the regulation of Pparg in bone, affecting both marrow adiposity and bone mass. Examination of the effects of Rosiglitazone, a pharmacological PPARG agonist, on bone, body composition and serum IGF-1 levels in a variety of inbred strains demonstrated that response to Rosiglitazone is a polygenetic trait. Furthermore, Rosiglitazone did not affect BMD in the 6T strain, but at a high dose did result in a decrease in BMD in B6 mice. This suggests that allelic differences in Pparg are in part responsible for the differential effect of this drug in bone. In summary, activation of PPARG by either dietary fat or Rosiglitazone differentially impacts bone in B6 and 6T mice and this may, at least in part, be controlled by Ccrn4l.

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