Several lines of evidence implicated the pathophysiological role of the endoplasmic reticulum (ER) stress in obesity-induced insulin resistance and diabetes. Using a targeted transcriptomic profiling approach consisting of the Heat Shock Response RT2 Profiler PCR Array, we previously reported impaired expression of DNAJB3/Hsp-40 cochaperone in obese and diabetic human subjects that was restored by physical exercise. In addition to DNAJB3/Hsp-40, three other genes showing differential expression between lean and obese human subjects were identified and GRP78 is the subject of our current investigation. Using histochemistry, immunofluorescence and western blots, our data show that GRP78 protein is increased in the adipose tissue obese subjects and thus, confirming the initial transcriptomic approach. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects and they correlated negatively with VO2, Max but positively with CRP and the obesity indicators such as BMI, body fat, and waist circumference. As GRP78 is the master regulator of the Unfolded Protein Response (UPR), we investigated the status of three arms of the UPR namely ATF6, IRE1a and PERK. Consistent with the finding on GRP78, our data indicated a marked increase in the expression and activity of these three arms in the adipose tissue from obese subjects. We finally tested the hypothesis that physical exercise could modulate the expression and release of GRP78 and its downstream targets. Here, we provide for the first evidence that physical attenuated significantly the endogenous expression and release of GRP78 with a concomitant reduction in the activity of IRE1a and eIF2a. Taken together, these results strongly suggest that exercise alleviated ER stress in obese subjects through attenuation of GRP78 signaling network.


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