The effects of allelic variation in Pparg on skeletal metabolism

Summary

Principal Investigator: Cheryl L Ackert-Bicknell
Abstract: [unreadable] DESCRIPTION (provided by applicant): Project summary: Currently 55% of American over the age of 50 have or are at risk for osteoporosis. The long term objective of this proposal is to characterize the impact of allelic variation in the Peroxisome Proliferator Activated Receptor Gamma (Pparg) gene on skeletal metabolism during activation of this nuclear receptor by dietary or synthetic ligand. The B6.C3H-6T (6T) mouse, a model of human age related bone loss, carries alleles from the C3H/HeJ strain for Pparg, on an otherwise C57BL/6J (B6) background, and has low Bone Mineral Density (BMD). Dietary fat is an activator of PPARG protein and has been found to interact with allelic variation in Pparg to influence BMD. More specifically, feeding a high fat diet results in low BMD in 6T but not B6 mice. A similar interaction has been found in humans. The first specific aim of this proposal is to identify and characterize the molecular pathways by which dietary fat impacts bone acquisition. Gene expression of key genes that affect or are targets of PPARG will be examined by high throughput Quantitative Real Time PCR (QPCR), in liver and femur from B6 and 6T mice fed a high or a low fat diet. Approximately 21 % of Americans over the age of 60 currently have diabetes. Thiazolidinediones (TZDs) are popular drugs for the treatment of Type II diabetes, are ligands for PPARG, and have been shown to negatively affect BMD. In the second specific aim, the in vivo consequences of PPARG activation by, Rosiglitazone (a TZD), will be characterized to determined the impact on skeletal maintenance. Groups of female B6 and 6T mice will be treated with Rosiglitazone (20 mg/kg/day) for 8 wks. Femurs will be collected and phenotyped for BMD, bone architecture and marrow adiposity. In a separate, but identically treated group of mice, bones and livers will be collected and the expression of key genes identified in Aim One will be examined by QPCR. The goal of this aim is to to ascertain differences and similarities between activation of PPARG by either dietary fat or Rosi. Insulin-like Growth factor-1 is a key growth factor for bone and in vitro is negatively regulated by PPARG. Treatment with Rosiglitazone will be expanded to include 5 inbred strains to determine if serum IGF-1 is a convenient surrogate marker for bone loss induced by Rosiglitazone. Relevance to Public Health: This research will determine why a high fat diet results in low bone density, in people carrying certain versions of the PPARG gene. In addition, Rosiglitazone is a common Type 2 Diabetes drug which acts on PPARG, but treatment with this drug may also decrease bone density. This research will determine if Rosiglitazone affects bone and under what circumstances. [unreadable] [unreadable] [unreadable]
Funding Period: 2007-07-07 - 2008-01-04
more information: NIH RePORT

Top Publications

  1. pmc A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-gamma nuclear translocation
    Masanobu Kawai
    The Musculoskeletal Laboratory, Maine Medical Center Research Institute, Scarborough, ME 04074, USA
    Proc Natl Acad Sci U S A 107:10508-13. 2010
  2. pmc PPARG by dietary fat interaction influences bone mass in mice and humans
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    J Bone Miner Res 23:1398-408. 2008
  3. pmc Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    Endocrinology 150:1330-40. 2009

Detail Information

Publications3

  1. pmc A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-gamma nuclear translocation
    Masanobu Kawai
    The Musculoskeletal Laboratory, Maine Medical Center Research Institute, Scarborough, ME 04074, USA
    Proc Natl Acad Sci U S A 107:10508-13. 2010
    ..These data illustrate a unique mechanism whereby a nutrient-responsive gene influences BMSCs differentiation, adipogenesis, and ultimately body composition...
  2. pmc PPARG by dietary fat interaction influences bone mass in mice and humans
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    J Bone Miner Res 23:1398-408. 2008
    ..These findings suggest that dietary fat has a significant influence on BMD that is dependent on the alleles present for the PPARG gene...
  3. pmc Strain-specific effects of rosiglitazone on bone mass, body composition, and serum insulin-like growth factor-I
    Cheryl L Ackert-Bicknell
    The Jackson Laboratory, Bar Harbor, Maine 04609, USA
    Endocrinology 150:1330-40. 2009
    ..The divergent skeletal responses to rosiglitazone in this study suggest the existence of a strong genetic background effect...