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


RESULTS
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
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.
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America. chenjinran@uams.edu
Jin-Ran
JR
Chen
Oxana P
OP
Lazarenko
Xianli
X
Wu
Yudong
Y
Tong
Michael L
ML
Blackburn
Kartik
K
Shankar
Thomas M
TM
Badger
Martin J J
MJ
Ronis
D000818:Animals; D015519:Bone Density; D002454:Cell Differentiation; D004041:Dietary Fats / Q000008:administration & dosage; D006128:Growth; D008297:Male; D009765:Obesity / Q000503:physiopathology*; D010006:Osteoblasts / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism*; D010289:Parenteral Nutrition, Total; D051381:Rats; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D004041:Dietary Fats; D047495:PPAR gamma; D051153:Wnt Proteins; D051176:beta Catenin