Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone

Abdelkrim Khadir, Sina Kavalakatt, Jehad Abubaker, Preethi Cherian, Dhanya Madhu, Irina Al-Khairi, Mohamed Abu-Farha, Samia Warsame, Naser Elkum, Mohammed Dehbi, Ali Tiss

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background and objectives Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Methods Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n = 40) and obese (n = 40, at baseline and after 3 months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT2 Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Results Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). Conclusion Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.

Original languageEnglish
Pages (from-to)1409-1420
Number of pages12
JournalMetabolism: Clinical and Experimental
Volume65
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Fingerprint

Endoplasmic Reticulum Stress
Unfolded Protein Response
Exercise
Endoplasmic Reticulum
Subcutaneous Fat
Inositol
Activating Transcription Factor 6
Obesity
Eukaryotic Initiation Factor-2
3T3-L1 Cells
Heat-Shock Response
Polymerase Chain Reaction
Waist Circumference
Enzymes
C-Reactive Protein
Protein Kinases
Fluorescent Antibody Technique
glucose-regulated proteins
Adipose Tissue
Homeostasis

Keywords

  • Adipose tissue
  • ER stress
  • GRP78
  • Obesity
  • Physical exercise

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. / Khadir, Abdelkrim; Kavalakatt, Sina; Abubaker, Jehad; Cherian, Preethi; Madhu, Dhanya; Al-Khairi, Irina; Abu-Farha, Mohamed; Warsame, Samia; Elkum, Naser; Dehbi, Mohammed; Tiss, Ali.

In: Metabolism: Clinical and Experimental, Vol. 65, No. 9, 01.09.2016, p. 1409-1420.

Research output: Contribution to journalArticle

Khadir, A, Kavalakatt, S, Abubaker, J, Cherian, P, Madhu, D, Al-Khairi, I, Abu-Farha, M, Warsame, S, Elkum, N, Dehbi, M & Tiss, A 2016, 'Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone', Metabolism: Clinical and Experimental, vol. 65, no. 9, pp. 1409-1420. https://doi.org/10.1016/j.metabol.2016.06.004
Khadir, Abdelkrim ; Kavalakatt, Sina ; Abubaker, Jehad ; Cherian, Preethi ; Madhu, Dhanya ; Al-Khairi, Irina ; Abu-Farha, Mohamed ; Warsame, Samia ; Elkum, Naser ; Dehbi, Mohammed ; Tiss, Ali. / Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. In: Metabolism: Clinical and Experimental. 2016 ; Vol. 65, No. 9. pp. 1409-1420.
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AU - Madhu, Dhanya

AU - Al-Khairi, Irina

AU - Abu-Farha, Mohamed

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AU - Elkum, Naser

AU - Dehbi, Mohammed

AU - Tiss, Ali

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N2 - Background and objectives Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Methods Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n = 40) and obese (n = 40, at baseline and after 3 months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT2 Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Results Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). Conclusion Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.

AB - Background and objectives Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. Methods Subcutaneous adipose tissue (SAT) and blood samples were collected from non-diabetic adult human lean (n = 40) and obese (n = 40, at baseline and after 3 months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT2 Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. Results Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high-sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1α and eukaryotic initiation factor-2α (eIF2α). Conclusion Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.

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