Endurance training in mice increases the unfolded protein response induced by a high-fat diet.

Certain conditions, such as several weeks of high-fat diet, disrupt endoplasmic reticulum (ER) homeostasis and activate an adaptive pathway referred as the unfolded protein response. When the unfolded protein response fails, the result is the development of inflammation and insulin resistance. These two pathological states are known to be improved by regular exercise training but the mechanisms remain largely undetermined. As it has recently been shown that the unfolded protein response is regulated by exercise, we hypothesised that concomitant treadmill exercise training (HFD+ex) prevents ER homeostasis disruption and its downstream consequences induced by a 6-week high-fat diet (HFD) in mice by activating the protective unfolded protein response. Several well-documented markers of the unfolded protein response were measured in the soleus and tibialis anterior muscles as well as in the liver and pancreas. In HFD mice, an increase in these markers was observed (from 2- to 15-fold, P < 0.05) in all tissues studied. The combination of HFD+ex increased the expression of several markers further, up to 100 % compared to HFD alone (P < 0.05). HFD increased inflammatory markers both in the plasma (IL-6 protein, 2.5 ± 0.52-fold; MIP-1α protein, 1.3 ± 0.13-fold; P < 0.05) and in the tissues studied, and treadmill exercise attenuated the inflammatory state induced by HFD (P < 0.05). However, treadmill exercise could not reverse HFD-induced whole body glucose intolerance, assessed by OGTT (AUC, 1.8 ± 0.29-fold, P < 0.05). In conclusion, our results show that a HFD activated the unfolded protein response in mouse tissues in vivo, and that endurance training promoted this response. We speculate that the potentiation of the unfolded protein response by endurance training may represent a positive adaptation protecting against further cellular stress.