Weight Cycling Creates an Obesogenic Memory in Adipose Tissue Which Exacerbates the Inflammatory Response to Obesity

Abstract

The obesity pandemic has continued to grow over the past few years, with over 44% of the adult world population estimated to be overweight. Energy expenditure through physical activity and dieting promotes weight loss which can lead to beneficial adaptations that promote healthy metabolism. However, few patients successfully manage to include physical activity in their daily routine and tend to weight cycle. The purpose of this study was to evaluate the inflammatory status of mice undergoing weight cycling. Male C57BL/6 mice were randomized into four groups: low fat diet for 32 weeks (LFD) (n=10), high fat diet for 32 weeks (HFD) (n=10), low fat diet for 28 weeks then changed to high fat for 4 weeks (LFD‐>H) (n=10), high fat diet for 21 weeks then changed to low fat for 7 weeks and then changed back to high fat for 4 weeks (HFD‐>L‐>H) (n=10). LFD‐>H and HFD‐>L‐>H mice did not significantly differ in body weight, body fat weight, or body fat percentage, but were significantly higher than LFD mice (p<0.05) while remaining lower than HFD mice (p<0.05) at the conclusion of the study. We measured the average adipocyte size of the epididymal fat pad and found that HFD‐>L‐>H mice had smaller adipocytes compared to HFD and LFD‐>H mice which both had significantly larger adipocytes (p<0.05) compared to LFD. Frequency analysis of adipocyte size revealed that LFD and HFD‐>L‐>H mice had significantly more small adipocytes (p<0.05) compared to HFD and LFD‐H mice. TNFa and IFNg were significantly higher (p<0.05) in the epididymal fat pad of HFD‐>L‐>H mice compared to LFD and LFD‐>H mice. However, MCP1 was significantly lower (p<0.05) in HFD‐>L‐>H mice compared to LFD‐>H. These trends in cytokines were complemented by more M1‐type macrophages (p<0.05) and cytotoxic T‐cells (p<0.05) in the epididymal fat as indicated by ITGAX and CD8a gene expression, respectively. Interestingly, there was no difference in total macrophages between LFD‐>H and HFD‐>L‐>H mice as indicated by EMR1 expression. Liver histopathological analysis revealed HFD‐>L‐>H mice had greater NASH (p<0.05) and NAS (p<0.05) scores compared to LFD controls, whereas LFD‐>H mice did not show any differences compared to LFD controls. Liver protein analysis showed increased total STAT3 (p<0.05) and NF‐kB (p<0.05) in HFD‐>L‐>H compared to LFD controls. Further, p‐AMPK (T172) was significantly increased (p<0.05) in all groups compared to LFD controls indicating metabolic stress was present in the livers, however there was no difference between LFD‐>H and HFD‐>L‐>H mice. Taken together, we have shown that weight cycling can lead to aberrations in the storage of triglycerides when challenged with an increased caloric intake. This is further supported by an increase in M1 type pro‐inflammatory macrophages in the epididymal fat tissue in weight cycling mice which is likely contributing to the observed obesogenic memory phenotype.