Deficiency of PPAR gamma in bone marrow stromal cells does not prevent high-fat diet-induced bone deterioration in mice

Authors: Cao, Jay; Gregoire, Brian; Michelsen, Kim; SHI, XINGMING - Augusta University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/5/2021
Publication Date: 6/10/2021
Citation: Cao, J.J., Gregoire, B.R., Michelsen, K.G., Shi, X. 2021. Deficiency of PPAR gamma in bone marrow stromal cells does not prevent high-fat diet-induced bone deterioration in mice. Journal of Nutrition. https://doi.org/10.1093/jn/nxab173.
DOI: https://doi.org/10.1093/jn/nxab173

Interpretive Summary: Obesity and osteoporosis are two common public health problems in the United States. Bone forming cells and fat cells are from a same stem cell origin. Existing evidence shows that decreasing bone marrow fat accumulation increases bone formation. Studies show that a protein called peroxisome proliferator-activated receptor gamma (PPAR gamma) is needed for fat cell development and may affect bone metabolism. In the current study, we developed an animal model with PPAR gamma gene deleted only from bone marrow cells and used this animal model to investigate the effects of a high-fat diet on bone in mice. We found that knockout PPAR gamma gene from bone marrow cells increased bone mass at tibia and did not prevent bone loss induced by the high-fat diet. Our results suggest that PPAR gamma does not play an significant role in bone loss in high-fat diet induced obese mice.

Technical Abstract: Obesity 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. PPAR 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. Compared 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. These data indicate PPAR gamma has site-specific impact on bone structure in mice and knockout PPAR gamma in BMSC increased bone mass in tibia likely through increased osteoblastogenesis. PPAR gamma disruption in BMSC did not prevent high-fat diet-induced bone deterioration in mice.