High-Fat Diet Causes Bone Loss in Young Mice by Promoting Osteoclastogenesis Through Alteration of the Bone Marrow Environment

Abstract

Obesity is a severe health problem in children, afflicting several organ systems including bone. However, the role of obesity on bone homeostasis and bone cell function in children has not been studied in detail. Here we used young mice fed a high-fat diet (HFD) to model childhood obesity and investigate the effect of HFD on the phenotype of cells within the bone marrow environment. Five-week-old male mice were fed a HFD for 3, 6, and 12 weeks. Decreased bone volume was detected after 3 weeks of HFD treatment. After 6 and 12 weeks, HFD-exposed mice had less bone mass and increased osteoclast numbers. Bone marrow cells, but not spleen cells, from HFD-fed mice had increased osteoclast precursor frequency, elevated osteoclast formation and bone resorption activity, as well as increased expression of osteoclastogenic regulators including RANKL, TNF, and PPAR-gamma. Bone formation rate and osteoblast and adipocyte numbers were also increased in HFD-fed mice. Isolated bone marrow cells also had a corresponding elevation in the expression of positive regulators of osteoblast and adipocyte differentiation. Our findings indicate that in juvenile mice, HFD-induced bone loss is mainly due to increased osteoclast bone resorption by affecting the bone marrow microenvironment. Thus, targeting osteoclast formation may present a new therapeutic approach for bone complications in obese children. 5Co-corresponding author: Xing, Lianping,

Diets High in Fat or Fructose Differentially Modulate Bone Health and Lipid Metabolism

“…In addition to altered trabecular bone properties with HF, here, we also observed a negative impact of HF on the cortical femur including decreased cortical thickness and TMD. The effects of high-fat feeding on trabecular bone observed in our study were modest compared to changes reported by others [12, 13, 32]. We speculate that some of the differences between studies may be accounted for by specific aspects of the diet (e.g., 45% fat content vs. 60%), differences in species (e.g., rat vs. mouse), or differences in genetic makeup within a species (e.g., BALB/c vs C57BL/6 mice).…”

“…Although obesity induced increases in body mass can act as growth factor on bone through augmented mechanical loading, high-fat diets can increase osteoclastogenesis, marrow adipogenesis, and decrease bone mass [12, 14]. Consumption of high-fat diets also increases circulating levels of the hormone leptin, a principal regulator of energy homeostasis that can impact bone growth [16].…”

“…Consumption of high-fat diets also increases circulating levels of the hormone leptin, a principal regulator of energy homeostasis that can impact bone growth [16]. HF diet causes preferential attrition of trabecular bone volume and architecture, with some investigations not observing negative effects on cortical bone [12–14, 22]. In addition to altered trabecular bone properties with HF, here, we also observed a negative impact of HF on the cortical femur including decreased cortical thickness and TMD.…”

“…High-fat diet (HFD) significantly alters the bone marrow microenvironment, causing accumulation of adipose tissue in the marrow, altering the lineage potential of stem cells and reducing the number of B-cells [9–11]. In male mice and despite of increased body mass, HFD may deteriorate trabecular bone volume and architecture without significantly impacting the cortical compartment [12–14]. Other investigations showed that HFD initially increases bone deposition due to increased mechanical demand but consequently impairs bone formation and turnover due to metabolic dysregulation [15].…”

Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner

“…The vast majority of studies have instead focused on the detrimental effects of high-fat diet feeding on skeletal homeostasis. In general, these studies have reported a reduction in bone mass secondary to reduced osteoblast activity and increased osteoclastic bone resorption (46)(47)(48)(49), as well as reduced sensitivity to anabolic hormones such as parathyroid hormone (PTH) (50).…”