The Effects Of A High-fat Diet And Exercise On The Pgc-1α-fndc5/irisin Pathway In C57bl/6 Mice

Abstract

Irisin has recently been identified as a novel protein that stimulates the “browning” of white adipose by inducing thermogenesis via increased uncoupling protein 1 (UCP1). Exercise, in a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) dependent manner, increases the release of the irisin precursor, fibronectin type III domain-containing protein 5 (FNDC5) from muscle. Irisin holds potential as a novel pharmacotherapeutic that could be used in the treatment of obesity. Prior studies have assessed the effects of exercise on irisin and proteins upstream and downstream of its activation, but the effects of diet on irisin have not been investigated. PURPOSE: The aim of this study was to evaluate the effects of diet and exercise on FNDC5 and associated proteins. METHODS: C57BL/6 mice were randomized into three groups for the 4 wk intervention: Mice were fed a standard diet (Std, n = 12), a high-fat diet (HF, n = 14), or fed a high-fat diet and housed individually with free access to a running wheel (HFEX, n = 14). At end study, mice were sacrificed, the gastrocnemius was harvested, and FNDC5, UCP1, and PGC-1α levels were measured by western blot and normalized to α-tubulin and reported as integrated density units. RESULTS: Body weight was greater in HF compared to Std (p < 0.001) and HFEX (p < 0.001) after the 4 wk intervention. (Std: 27.1 ± 1.7; HF: 30.4 ± 2.3; HFEX: 27.1 ± 1.9 g). There was a trend (p = 0.09) toward increased FNDC5 levels in HF compared to HFEX (HF: 0.73 ± 0.08 vs. HFEX: 0.51 ± 0.08). UCP1 levels were significantly lower (p < 0.05) in the HFEX (0.66 ± 0.11) compared to both Std (1.2 ± 0.19) and HF (1.1 ± 0.24). There were no significant differences among groups in PGC-1α (Std: 0.93 ± 0.17, HF: 0.77 ± 0.13, HFEX: 1.2 ± 0.36). CONCLUSION: Although there were no statistically significant differences in FNDC5 levels, the trend toward increased FNDC5 in HF compared to HFEX suggests increased FNDC5 may be a compensatory mechanism to offset HF diet-induced weight gain by increasing energy expenditure. Exercise prevented excess weight gain in HF fed mice, but these effects do not appear to be mediated by increased FNDC5 levels. Further investigation, including assessment of FNDC5, PGC1-α, and UCP1 levels in adipose from these mice will be performed to confirm the effects of HF feeding on the FNDC5/irisin pathway.