Interleukin-6 gene knockout antagonizes high-fat-induced trabecular bone loss

Abstract

The purpose of the study was to determine the roles of interleukin-6 (IL6) in fat and bone communication. Male wild-type (WT) mice and IL6 knockout (IL6 −/− ) mice were fed with either regular diet (RD) or high-fat diet (HFD) for 12 weeks. Bone mass and bone microstructure were evaluated by micro-computed tomography. Gene expression related to lipid and bone metabolisms was assayed with real-time quantitative polymerase chain reaction. Bone marrow cells from both genotypes were induced to differentiate into osteoblasts or osteoclasts, and treated with palmitic acid (PA). HFD increased the body weight and fat pad weight, and impaired lipid metabolism in both WT and IL6 −/− mice. The dysregulation of lipid metabolism was more serious in IL6 −/− mice. Trabecular bone volume fraction, trabecular bone number and trabecular bone thickness were significantly downregulated in WT mice after HFD than those in the RD (P < 0.05). However, these bone microstructural parameters were increased by 53%, 34% and 40%, respectively, in IL6 −/− mice than those in WT mice on the HFD (P < 0.05). IL6 −/− osteoblasts displayed higher alkaline phosphatase (ALP) activity and higher mRNA levels of Runx2 and Colla1 than those in WT osteoblasts both in the control and PA treatment group (P < 0.05). IL6 −/− mice showed significantly lower mRNA levels of PPARγ and leptin and higher mRNA levels of adiponectin in comparison with WT mice on HFD. In conclusion, these findings suggested that IL6 gene deficiency antagonized HFD-induced bone loss. IL6 might bridge lipid and bone metabolisms and could be a new potential therapeutic target for lipid metabolism disturbance-related bone loss.

Effects of High-Fat Diet and Body Mass on Bone Morphology and Mechanical Properties in 1100 Advanced Intercross Mice

“…Although we did not assess metabolic outcomes here, in mice from the F 16 generation of the LG,SM AI line, a high‐fat diet led to reduced glucose tolerance and elevated serum insulin . Others have reported that trabecular bone loss induced by a high‐fat diet is modulated via the effects of inflammatory cytokines TNF‐α and IGF‐1 . These competing effects—increased bone formation due to increased body weight versus a prediabetic condition that may inhibit bone formation and/or enhance resorption—are consistent with our overall finding that a high‐fat diet was good for bone in absolute terms (ie, associated with absolute increases in bone size and whole‐bone strength) but was relatively detrimental if we account for body size.…”

“…(22,40) Others have reported that trabecular bone loss induced by a high-fat diet is modulated via the effects of inflammatory cytokines TNF-a and IGF-1. (41,42) These competing effects-increased bone formation due to increased body weight versus a prediabetic condition that may inhibit bone formation and/or enhance resorption-are consistent with our overall finding that a high-fat diet was good for bone in absolute terms (ie, associated with absolute increases in bone size and whole-bone strength) but was relatively detrimental if we account for body size. We note that these findings may be different in older mice that become obese as adults or that continue to consume a highfat diet after reaching skeletal maturity.…”

The Unique Metabolic Characteristics of Bone Marrow Adipose Tissue

“…However, another research reported that human BM adipocytes in primary culture secrete only little amounts of IL1-β and TNF-α, but significant levels of IL-6 (114). Whatever, the BM adipocytes have a great potential to secrete pro-inflammatory factors, which may regulate bone metabolism (115, 116) and haematopoiesis (117) through paracrine, as well as affect the whole body metabolism by entering into the circulation.…”

Marrow Fat-Secreted Factors as Biomarkers for Osteoporosis

“…Although many open questions remain, pro-inflammatory cytokines are likely to mediate at least partially the detrimental effects of bone marrow adiposity [130,131].…”