High‐fat diet alters body composition and serum cytokines before the overt onset of obesity

Abstract

Rising trends in childhood obesity are related, in part, to increased dietary fat intake. Accelerated bone growth, a hallmark of juvenile obesity but one of its most overlooked complications, can lead to irreversible skeletal damage and chronic adult disability. Paradoxically, obese children typically have low to normal levels of the growth promoting hormone insulin-like growth factor-1 (IGF-1), despite their accelerated growth rate. Obesity is characterized by chronic inflammation driven by cytokines such as interleukin-6 (IL-6) which can suppress bone elongation by inhibiting IGF-1. We previously found that a high-fat diet increases bone growth and alters serum cytokines in young male and female mice before significant changes in body mass were evident. Our goal here was to determine whether excess body fat could explain the increase in bone elongation rate when overall body mass remains similar. We tested the hypothesis that mice on a high-fat diet exhibit changes in body composition along with higher levels of inflammatory cytokines before they develop overt obesity. Methods Male 3-week-old C57BL/6 mice (N=6/diet) were put on high-fat (60% kCal fat) or control (10% kCal fat) diet for 2 weeks after weaning. Serum cytokines (Leptin, TNF-α, IGF-1, IL-6, VEGF, IL-1α, IL-1β, MCP-1) were measured by ELISA. Skinfold thickness in the rump region was measured in a separate group of mice using a dial micrometer to estimate body fat. Statistical significance (p<0.05) was determined in SPSS using Mann-Whitney and t-tests. Results After only 2 weeks, tibial elongation rate was over 10% higher in mice on a high-fat diet (t=2.1, p<0.05), but had no difference in body mass (t=0.5, p=0.62). Among the cytokines measured, TNF-α (z=2.9, p<0.01) and IL-6 (z=2.7, p<0.01) were both decreased in the high-fat diet group, while VEGF (z=2.7, p<0.01) was increased. Rump skinfold was nearly 7% greater (t=2.6, p<0.05) in the high-fat diet group, indicating a higher proportion of body fat. Discussion Our results support the hypothesis that a high-fat diet alters body composition and inflammatory cytokines before overt signs of obesity. Unexpectedly, the most robust change was a 1.5-fold decrease in IL-6, rather than the increase that we had predicted. Since elevated levels of IL-6 suppress growth, our findings of decreased IL-6 are consistent with accelerated bone lengthening. IL-6 also has a role in energy metabolism, and so the changes in body composition that we observed (increased subcutaneous fat) might play a role in altering serum cytokines. Significance These results are relevant for understanding the development of obesity-related skeletal complications. Reduced inflammatory cytokines such as IL-6 could serve as a useful biomarker of potential adverse effects, providing the opportunity to implement interventions to mitigate long-term skeletal damage before it might otherwise be recognized.