Location: Arkansas Children's Nutrition CenterTitle: Obesity reduces bone density through activation of PPAR gamma and suppression of Wnt/Beta-Catenin in rapidly growing male rats) Author
Submitted to: PLoS One
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/5/2010
Publication Date: 10/28/2010
Citation: Chen, J., Lazarenko, O.P., Wu, X., Tong, Y., Blackburn, M.L., Shankar, K., Badger, T.M., Ronis, M.J. 2010. Obesity reduces bone density through activation of PPAR Gamma and suppression of Wnt/Beta-Catenin in rapidly growing male rats. PLoS One. 5(10):e13704. Interpretive Summary: The effect of excessive consumption of high fat diet (HFD) and of obesity itself, on bone development and maturation remain largely unclear particularly in children. In this report, we chronically fed HFD containing 25% or 45% fat diet, to male Sprague-Dawley rats for 4 weeks beginning at weaning, and rats became obese based on increased their body fat accumulation. Bone quality was significantly poor in HFD animals compared to their controls. We found that five major free fatty acids; palmitic, stearic, oleic, linoleic, and arachidonic acid in the ratio of 5:3:1:3:1, were 5 times higher in concentration in rat serum from 45% fat HFD-fed compared to control rats. Fat was also accumulated in bone marrow. These observations suggest that increased free fatty acids in serum from HFD-fed rats directly impaired bone formation due to stimulation of bone marrow adipocyte systhesis. These effects of HFD-feeding on bone in early life may result in impaired attainment of peak bone mass and therefore increase the prevalence of osteoporosis later on in life.
Technical Abstract: The relationship between obesity and skeletal development remains largely ambiguous. In this report, total enteral nutrition (TEN) was used to feed growing male rats intragastrically, with a high 45% fat diet (HFD) to induce obesity. We found that fat mass was increased (P<0.05) compared to rats fed TEN diets, containing 25% fat or a chow diet (LFD) fed ad libitum with matched body weight gains. Serum leptin and total non-esterified fatty acids (NEFA) were elevated in HFD rats, which also had reduced bone mass compared to LFD-fed animals. This was accompanied by decreases in the serum bone formation marker osteocalcin, but increases in the bone resorption marker RatLaps. Bone marrow adiposity and expression of adipogenic genes, PPAR' and aP2 were increased, whereas osteoblastogenic markers osteocalcin and Runx2 were decreased, in bone in HFD rats compared to LFD controls (P<0.05). The diversion of stromal cell differentiation in response to HFD, stemmed from down-regulation of the key canonical Wnt signaling molecule beta-catenin protein and reciprocal up-regulation of nuclear PPAR gamma expression in bone. In a set of in vitro studies using pluripotent ST2 mesenchymal stem cells, treated with serum from rats on the different diets or using the free fatty acid composition of NEFA quantified in rat serum from HFD-fed animals by GC-MS, we were able to recapitulate our in vivo findings. These observations strongly suggest that increased NEFA in serum from rats, made obese by HFD-feeding directly impaired bone formation due to stimulation of bone marrow adipogenesis. These effects of obesity on bone in early life may result in impaired attainment of peak bone mass therefore, increasing the prevalence of osteoporosis later on in life.