Abstract
Chronic high-fat diet (HFD) consumption not only promotes obesity and insulin resistance, but also causes bone loss through mechanisms that are not well understood. Here, we fed wild-type CD-1 mice either chow or a HFD (43% of energy from fat) for 18 weeks; HFD-fed mice exhibited decreased trabecular volume (−28%) and cortical thickness (−14%) compared to chow-fed mice. In HFD-fed mice, bone loss was due to reduced bone formation and mineral apposition, without obvious effects on bone resorption. HFD feeding also increased skeletal expression of sclerostin and caused deterioration of the osteocyte lacunocanalicular network (LCN). In mice fed HFD, skeletal glucocorticoid signaling was activated relative to chow-fed mice, independent of serum corticosterone concentrations. We therefore examined whether skeletal glucocorticoid signaling was necessary for HFD-induced bone loss, using transgenic mice lacking glucocorticoid signaling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice). In HSD2OB/OCY-tg mice, bone formation and mineral apposition rates were not suppressed by HFD, and bone loss was significantly attenuated. Interestingly, in HSD2OB/OCY-tg mice fed HFD, both Wnt signaling (less sclerostin induction, increased β-catenin expression) and glucose uptake were significantly increased, relative to diet- and genotype-matched controls. The osteocyte LCN remained intact in HFD-fed HSD2OB/OCY-tg mice. When fed a HFD, HSD2OB/OCY-tg mice also increased their energy expenditure and were protected against obesity, insulin resistance, and dyslipidemia. Therefore, glucocorticoid signaling in osteoblasts and osteocytes contributes to the suppression of bone formation in HFD-fed mice. Skeletal glucocorticoid signaling is also an important determinant of glucose uptake in bone, which influences the whole-body metabolic response to HFD.
Highlights
Chronic consumption of high-fat diets (HFDs), those high in saturated fat, leads to obesity,[1] insulin resistance,[2] and dyslipidemia[3] and produces a marked deterioration in bone structure, mass, and strength.[4,5,6,7,8,9,10,11] studies in humans have shown that higher dietary saturated fat intake is associated with lower bone mineral density and increased fracture risk in both men and women.[12,13]Bone loss in mice fed HFDs (deriving up to 60% of energy from fat) is thought to result from either excessive bone resorption,[4,6] reduced bone formation,[10,11] or a combination of the two,[8] with the effects generally being more pronounced in younger mice.[14,15]Glucocorticoids are steroid hormones that mediate the physiological response to stress[16] and have deleterious effects on bone structure and quality
high-fat diet (HFD) feeding increased local glucocorticoid signaling in bone Here, we studied male mice with disrupted glucocorticoid signaling in mature osteoblasts and osteocytes (HSD2OB/OCY-tg mice) and their wild-type littermates, both on a CD-1 background
Gilz/Tsc22d3 mRNA was induced by HFD feeding in wild-type mice, but there was no effect in HSD2OB/OCY-tg mice (Fig. 1c)
Summary
Chronic consumption of high-fat diets (HFDs), those high in saturated fat, leads to obesity,[1] insulin resistance,[2] and dyslipidemia[3] and produces a marked deterioration in bone structure, mass, and strength.[4,5,6,7,8,9,10,11] studies in humans have shown that higher dietary saturated fat intake is associated with lower bone mineral density and increased fracture risk in both men and women.[12,13]Bone loss in mice fed HFDs (deriving up to 60% of energy from fat) is thought to result from either excessive bone resorption,[4,6] reduced bone formation,[10,11] or a combination of the two,[8] with the effects generally being more pronounced in younger mice.[14,15]Glucocorticoids are steroid hormones that mediate the physiological response to stress[16] and have deleterious effects on bone structure and quality. HFD feeding induced skeletal Hsd11b1 mRNA expression in wild-type mice but not in HSD2OB/OCY-tg mice (Fig. 1b).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
