|Chen, Jinran -|
|Zhang, Jian -|
|Lazarenko, Oxana -|
|Cao, Jay -|
|Blackburn, Michael -|
|Ronis, Martin -|
Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 14, 2013
Publication Date: September 1, 2013
Citation: Chen, J., Zhang, J., Lazarenko, O.P., Cao, J.J., Blackburn, M.L., Badger, T.M., Ronis, M.J. 2013. Soy protein isolates prevent loss of bone quantity associated with obesity in rats through regulation of insulin signaling in osteoblasts. Journal of Federation of American Societies for Experimental Biology. 27(9):3514-3523. Interpretive Summary: Children (or adults) who consume a high fat diet increase their risk for obesity and many other chronic diseases including chronic bone disorder. However, mechanisms of the effects of such a high fat diet on bone development are poorly understood. In the current study, using a rat animal model, we fed young rapidly growing rats a high fat diet for 6 weeks starting from 21 days of age. We showed that rats became obese and had lower bone mineral density (BMD), significant accumulation of adipose tissue in bone marrow, and insulin resistance after high fat diet feeding. When rats were fed a high fat diet together with supplementation of soy protein isolate (SPI), all above observed effects of high fat diet disappeared. Protection of bone growth by soy protein isolate supplementation was associated with increased activity of osteoblasts, known as bone-forming cells in the body. The soy protein isolate-supplemented diet blocked fat tissue to secrete free fatty acids. These results suggest that the protective effects of the soy protein isolate diet on the skeleton after high fat diet feeding are due to suppression of serum free fatty acids to preserve insulin signaling in bone.
Technical Abstract: In both rodents and humans, excessive consumption of a typical Western diet high in saturated fats and cholesterol during postnatal life is known to result in disruption of energy metabolism, development of obesity and of insulin resistance. However, how these high fat, energy dense diets affect bone development, morphology and modeling is poorly understood. Here, we show that male weanling rats fed a diet containing 45% fat and 0.5% cholesterol made with casein (HF-Cas) for 6 weeks displayed a significant increase in bone marrow adiposity, and insulin resistance. Substitution of casein with soy protein isolate (SPI) in the high fat diet (HF-SPI) prevented these effects. Maintenance of bone quality in the SPI-fed rats was associated with increased undercarboxylated osteocalcin secretion and altered JNK/IRS1/Akt insulin signaling in osteoblasts. The HF-Cas group had significantly greater serum non-esterified free fatty acid (NEFA) concentrations than controls; whereas, the HF-SPI group prevented this increase. In vitro treatment of osteoblasts or mesenchymal stromal ST2 cells with NEFA significantly decreased insulin signaling. An isoflavone mixture similar to that found in serum of HF-SPI rats significantly increased in vitro osteoblast proliferation and blocked significantly reduced NEFA-induced insulin resistance. Finally, we showed that insulin/IGF1 was able to increase both osteoblast activity and differentiation in a set of in vitro studies. These results suggest that: 1) high fat feeding may disrupt bone development and modeling; 2) high concentrations of NEFA and insulin resistance occurring with high fat intake are mediators of reduced osteoblast activity and differentiation; 3) diets high in soy protein may help prevent high dietary fat-induced bone impairments; 4) the molecular mechanisms underlying the SPI-protective effects involve isoflavone-induced normalization of insulin signaling in bone.