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United States Department of Agriculture

Agricultural Research Service

Research Project: IMPACT OF EARLY DIETARY FACTORS ON CHILD DEVELOPMENT AND HEALTH

Location: Arkansas Children's Nutrition Center

Title: High fat diet-induced obesity reduces bone formation through activation of ppar gamma to suppress wnt/beta-catenin signaling in prepubertal rats

Authors
item Chen, Jinran -
item Lazarenko, Oxana -
item Shankar, Kartik -
item Wu, Xianli -
item Badger, Thomas
item Ronis, Martin -

Submitted to: American Society for Bone and Mineral Research
Publication Type: Abstract Only
Publication Acceptance Date: August 12, 2010
Publication Date: June 15, 2011
Citation: Chen, J., Lazarenko, O.P., Shankar, K., Wu, X., Badger, T.M., Ronis, M.J. 2011. High fat diet-induced obesity reduces bone formation through activation of ppar gamma to suppress wnt/beta-catenin signaling in prepubertal rats [abstract]. Journal of Bone and Mineral Research. 25(S1):S283.

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 percent or 45 percent fat diet to male Sprague-Dawley rats for 4 weeks beginning at weaning and rats became obese based on increasing 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 percent 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 synthesis. 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 effects of a high fat diet (HFD) and of obesity on skeletal development, maturation and remodeling remain largely unclear particularly in children. In this report, we utilized a total enteral nutrition (TEN) model to examine the direct effect of HFD feeding on bone prior to puberty. We chronically fed HFD containing 25 percent or 45 percent fat calories via TEN to male Sprague-Dawley rats for 4 weeks beginning at weaning. Body weight gains were matched between HFD-fed rats and rats fed a low fat chow diet (LFD) ad libitum. Both gonadal and abdominal fat mass were increased in HFD-fed animals compared to the LFD group (P less than 0.05). In addition, leptin and total non-esterified fatty acids (NEFA) were elevated in the HFD groups (P less than 0.05). HFD-feeding reduced total bone mineral content (BMC) and trabecular bone mineral density (BMD) compared to LFD-fed animals (P less than 0.05). This was accompanied by decreases in the serum bone formation marker osteocalcin, but increases in the bone resorption marker RatLaps (P less than 0.05). NEFA composition in serum from HFD and LFD-fed rats was characterized and quantified by a Shimazu QP-2010 GC-MS system after TLC separation. 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 percent fat HFD-fed compared to LFD-fed rats. Consistent with an increase in bone marrow adiposity, increased adipogenic gene PPAR' and AP2 expression was measured in bone from HFD-fed compared to LFD-fed rats (P less than 0.05). In contrast osteoblastogenic gene osteocalcin and Runx2 expression was reduced in bone tissue from the HFD-fed group compared to HFD-fed group (P less than 0.05). Impaired osteoblastogenic stromal cell differentiation in the HFD-fed rats 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 (P less than 0.05). In a set of in vitro studies using pluripotent ST2 mesenchymal stem cells (MSCs) treated with serum from rats on the different diets or using a mixture of free fatty acids based on the ratio appearing in serum from HFD-fed rats, we were able to recapitulate our in vivo findings These observations strongly suggest that increased NEFA in serum from HFD-fed rats directly impaired bone formation due to stimulation of bone marrow adipogenesis. 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.

Last Modified: 8/30/2014
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