Three weeks voluntary running wheel exercise increases endoplasmic reticulum stress in the brain of mice

The unfolded protein response (UPR) is a dynamic cellular mechanism for reducing endoplasmic reticulum (ER) stress. ER stress occurs from a variety of causes such as nutritional deprivation or over-nutrition, expression of misfolded or mutant proteins and increased synthesis of secretory protein. Obesity induced by over-nutrition has been associated with ER stress. Although exercise has a beneficial effect in opposing the development of obesity and neurodegenerative diseases, there have been no studies on the effect of exercise on ER stress in the brain induced by over-nutrition. We have taken advantage of the substantial individual differences in voluntary running activity among inbred C57BL/6 mice to investigate the relation between ER stress within regions of the brain and voluntary running activity in mice fed on either a low fat or high fat diet while maintained individually in cages with running wheels. Mice were divided into three groups depending on their voluntary running level and compared with a sedentary group. ER stress was assayed by real-time PCR and Western blots of the UPR pathway markers Xbp1, PERK, eIF2alpha, Hspa5 and ATF6. Three weeks of HFD had little effect on ER stress in the brain of the sedentary group compared to animals fed the LFD. Higher voluntary running activity was associated with increased ER stress in the hypothalamus, hippocampus and cortex. The responses were largest in the hypothalamus. The increase in the UPR response in response to exercise did not induce apoptotic signals and may thus contribute to the protective effect of exercise in preventing neurodegenerative disease.