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Obesity reduces bone density associated with activation of PPARγ and suppression of Wnt/β-catenin in rapidly growing male rats.

Chen JR, Lazarenko OP, Wu X, Tong Y, Blackburn ML, Shankar K, Badger TM, Ronis MJ - PLoS ONE (2010)

Bottom Line: This was accompanied by decreases in bone formation, but increases in the bone resorption.The diversion of stromal cell differentiation in response to HFD stemmed from down-regulation of the key canonical Wnt signaling molecule β-catenin protein and reciprocal up-regulation of nuclear PPARγ expression in bone.These effects of obesity 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America. chenjinran@uams.edu

ABSTRACT

Background: It is well established that excessive consumption of a high fat diet (HFD) results in obesity; however, the consequences of obesity on postnatal skeletal development have not been well studied.

Methodology and principal findings: Total enteral nutrition (TEN) was used to feed postnatal day 27 male rats intragastrically with a high 45% fat diet (HFD) for four weeks to induce obesity. Fat mass was increased compared to rats fed TEN diets containing 25% fat (medium fat diet, MFD) or a chow diet (low fat 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 bone formation, but increases in the bone resorption. Bone marrow adiposity and expression of adipogenic genes, PPARγ and aP2 were increased, whereas osteoblastogenic markers osteocalcin and Runx2 were decreased, in bone in HFD rats compared to LFD controls. The diversion of stromal cell differentiation in response to HFD stemmed from down-regulation of the key canonical Wnt signaling molecule β-catenin protein and reciprocal up-regulation of nuclear PPARγ expression in bone. In a set of in vitro studies using pluripotent ST2 bone marrow mesenchymal stromal 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.

Conclusions/significance: These observations strongly suggest that increased NEFA in serum from rats made obese by HFD-feeding 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 and therefore increase the prevalence of osteoporosis later on in life.

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Effect of increasing dietary fat on body weight and composition in male rats.LFD, low fat diet (control pelleted AIN-93G 14% fat diet); MFD, medium fat TEN diet (25% fat diet); HFD, high fat TEN diet (45% fat diet). (A), growth curves from three different diet groups. (B), visceral (gonadal fat) % body weight and (C), abdominal fat % body weight (D), Representative pseudocolored images of tibial peripheral quantitative CT scans (pQCT) (slice 3) from LFD, MFD and HFD rats. Color changes from blue, yellow, red, to gray represent decreases in bone density. Decreased bone mass in male rats fed HFD can be visualized. (E), total tibial bone mineral content (BMC). (F), tibial trabecular bone mineral density (BMD). (G), total tibial BMD. (H), tibial cortical BMD. Data bars are expressed as mean ± SEM (n = 6/group). Means with different letters differ significantly from each other at P<0.05, a<b<c as determined by two-way ANOVA followed by Student-Newman-Keuls post hoc analysis for multiple pairwise comparisons.
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pone-0013704-g001: Effect of increasing dietary fat on body weight and composition in male rats.LFD, low fat diet (control pelleted AIN-93G 14% fat diet); MFD, medium fat TEN diet (25% fat diet); HFD, high fat TEN diet (45% fat diet). (A), growth curves from three different diet groups. (B), visceral (gonadal fat) % body weight and (C), abdominal fat % body weight (D), Representative pseudocolored images of tibial peripheral quantitative CT scans (pQCT) (slice 3) from LFD, MFD and HFD rats. Color changes from blue, yellow, red, to gray represent decreases in bone density. Decreased bone mass in male rats fed HFD can be visualized. (E), total tibial bone mineral content (BMC). (F), tibial trabecular bone mineral density (BMD). (G), total tibial BMD. (H), tibial cortical BMD. Data bars are expressed as mean ± SEM (n = 6/group). Means with different letters differ significantly from each other at P<0.05, a<b<c as determined by two-way ANOVA followed by Student-Newman-Keuls post hoc analysis for multiple pairwise comparisons.

Mentions: TEN was utilized to tightly match body weight gains in all three diet groups. However, after 4 weeks of feeding, gonadal and retroperitoneal adipose tissue (percent body weight) differed and was lowest in the LFD group and highest in the HFD group (P<0.05) (Figure 1). Trabecular BMC was lower (P<0.05) in the HFD compared to either the LFD control or MFD groups (Figure 1E). Importantly, trabecular BMD was inversely associated with dietary fat content and the observed retroperitoneal and gonadal fat accumulation independent of body weight (Figure 1F). There were no differences in total and cortical BMD among groups (Figure 1G, H) indicating that short term HFD-induced obesity may initially effect trabecular bone compartment, a site of relatively high bone turnover, before eventually effecting total and cortical BMD.


Obesity reduces bone density associated with activation of PPARγ and suppression of Wnt/β-catenin in rapidly growing male rats.

Chen JR, Lazarenko OP, Wu X, Tong Y, Blackburn ML, Shankar K, Badger TM, Ronis MJ - PLoS ONE (2010)

Effect of increasing dietary fat on body weight and composition in male rats.LFD, low fat diet (control pelleted AIN-93G 14% fat diet); MFD, medium fat TEN diet (25% fat diet); HFD, high fat TEN diet (45% fat diet). (A), growth curves from three different diet groups. (B), visceral (gonadal fat) % body weight and (C), abdominal fat % body weight (D), Representative pseudocolored images of tibial peripheral quantitative CT scans (pQCT) (slice 3) from LFD, MFD and HFD rats. Color changes from blue, yellow, red, to gray represent decreases in bone density. Decreased bone mass in male rats fed HFD can be visualized. (E), total tibial bone mineral content (BMC). (F), tibial trabecular bone mineral density (BMD). (G), total tibial BMD. (H), tibial cortical BMD. Data bars are expressed as mean ± SEM (n = 6/group). Means with different letters differ significantly from each other at P<0.05, a<b<c as determined by two-way ANOVA followed by Student-Newman-Keuls post hoc analysis for multiple pairwise comparisons.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965663&req=5

pone-0013704-g001: Effect of increasing dietary fat on body weight and composition in male rats.LFD, low fat diet (control pelleted AIN-93G 14% fat diet); MFD, medium fat TEN diet (25% fat diet); HFD, high fat TEN diet (45% fat diet). (A), growth curves from three different diet groups. (B), visceral (gonadal fat) % body weight and (C), abdominal fat % body weight (D), Representative pseudocolored images of tibial peripheral quantitative CT scans (pQCT) (slice 3) from LFD, MFD and HFD rats. Color changes from blue, yellow, red, to gray represent decreases in bone density. Decreased bone mass in male rats fed HFD can be visualized. (E), total tibial bone mineral content (BMC). (F), tibial trabecular bone mineral density (BMD). (G), total tibial BMD. (H), tibial cortical BMD. Data bars are expressed as mean ± SEM (n = 6/group). Means with different letters differ significantly from each other at P<0.05, a<b<c as determined by two-way ANOVA followed by Student-Newman-Keuls post hoc analysis for multiple pairwise comparisons.
Mentions: TEN was utilized to tightly match body weight gains in all three diet groups. However, after 4 weeks of feeding, gonadal and retroperitoneal adipose tissue (percent body weight) differed and was lowest in the LFD group and highest in the HFD group (P<0.05) (Figure 1). Trabecular BMC was lower (P<0.05) in the HFD compared to either the LFD control or MFD groups (Figure 1E). Importantly, trabecular BMD was inversely associated with dietary fat content and the observed retroperitoneal and gonadal fat accumulation independent of body weight (Figure 1F). There were no differences in total and cortical BMD among groups (Figure 1G, H) indicating that short term HFD-induced obesity may initially effect trabecular bone compartment, a site of relatively high bone turnover, before eventually effecting total and cortical BMD.

Bottom Line: This was accompanied by decreases in bone formation, but increases in the bone resorption.The diversion of stromal cell differentiation in response to HFD stemmed from down-regulation of the key canonical Wnt signaling molecule β-catenin protein and reciprocal up-regulation of nuclear PPARγ expression in bone.These effects of obesity 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America. chenjinran@uams.edu

ABSTRACT

Background: It is well established that excessive consumption of a high fat diet (HFD) results in obesity; however, the consequences of obesity on postnatal skeletal development have not been well studied.

Methodology and principal findings: Total enteral nutrition (TEN) was used to feed postnatal day 27 male rats intragastrically with a high 45% fat diet (HFD) for four weeks to induce obesity. Fat mass was increased compared to rats fed TEN diets containing 25% fat (medium fat diet, MFD) or a chow diet (low fat 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 bone formation, but increases in the bone resorption. Bone marrow adiposity and expression of adipogenic genes, PPARγ and aP2 were increased, whereas osteoblastogenic markers osteocalcin and Runx2 were decreased, in bone in HFD rats compared to LFD controls. The diversion of stromal cell differentiation in response to HFD stemmed from down-regulation of the key canonical Wnt signaling molecule β-catenin protein and reciprocal up-regulation of nuclear PPARγ expression in bone. In a set of in vitro studies using pluripotent ST2 bone marrow mesenchymal stromal 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.

Conclusions/significance: These observations strongly suggest that increased NEFA in serum from rats made obese by HFD-feeding 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 and therefore increase the prevalence of osteoporosis later on in life.

Show MeSH
Related in: MedlinePlus