Deficiency of PPAR Gamma in Bone Marrow Stromal Cells Does Not Prevent High-Fat Diet-Induced Bone Deterioration in Mice

Abstract

ObjectivesObesity is detrimental to bone health in humans and in high-fat diet-induced obese animals. Bone marrow osteoblasts and adipocytes are derived from a common mesenchymal stem cell and have a reciprocal relationship. Peroxisome proliferator-activated receptor gamma (PPAR gamma), a regulator for adipocyte differentiation, may be a potential target for reducing obesity and increasing bone mass. This study tested the hypothesis that bone-specific PPAR gamma conditional knockout (cKO), via deletion of PPAR gamma gene from bone marrow stromal cells (BMSC) using Osterix 1 (Osx1)-Cre, would prevent high-fat diet-induced bone deterioration in mice. MethodsPPAR gamma cKO (PPAR gammafl/fl: Osx1–Cre) and floxed littermate control (PPAR gammafl/fl Osx1-P-Cre-) mice at 6-wk-old were randomly assigned to 4 groups (n = 12/group, 6 male and 6 female) and fed ad libitum either a normal-fat purified diet (NF, 3.85 kcal/g, 10% energy as fat) or a high-fat diet (HF, 4.73 kcal/g) for 6 mo. Bone structure, body composition, and serum bone-related cytokines were measured. ResultsCompared to the NF diet, the HF diet increased body mass and fat mass (P < 0.05) but not lean mass. The HF diet also decreased tibial and lumbar vertebrae trabecular volume/total volume (BV/TV) and bone mineral density (BMD) in both control and PPAR gamma cKO mice. PPAR gamma cKO mice had lower body fat mass and lean mass than control mice. PPAR gamma cKO mice had greater tibial trabecular BV/TV, trabecular number, connectivity density, and BMD and lower structure model index, compared to control mice. None of trabecular bone parameters at 2nd lumbar vertebrae was affected by genotype. PPAR gamma cKO mice had lower cortical medullary area, compared to control mice. PPAR gamma cKO mice had lower (P < 0.01) serum concentration of leptin and higher (P < 0.05) concentration of osteocalcin, compared with control mice. ConclusionsThese data indicate that PPAR gamma has site-specific impact on bone structure in mice and that knockout PPAR gamma in BMSC increased bone mass in tibia likely through increased osteoblastogenesis. However, PPAR gamma disruption in BMSC did not prevent high-fat diet-induced bone deterioration in mice. Funding SourcesUSDA-ARS #3062-51,000-053-00D.