title: Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone.
abstract: 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.
  
  
  
  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 3months 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 RT(2) 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.
  
  
  
  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).
  
  
  
  Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network.
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Abdelkrim
authors: A
authors: Khadir
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Sina
authors: S
authors: Kavalakatt
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Jehad
authors: J
authors: Abubaker
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Preethi
authors: P
authors: Cherian
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Dhanya
authors: D
authors: Madhu
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Irina
authors: I
authors: Al-Khairi
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Mohamed
authors: M
authors: Abu-Farha
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait.
authors: Samia
authors: S
authors: Warsame
authors: Clinical Epidemiology, Sidra Medical and Research Center, Doha, Qatar.
authors: Naser
authors: N
authors: Elkum
authors: Diabetes Research Centre, Qatar Biomedical Research Institute and Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
authors: Mohammed
authors: M
authors: Dehbi
authors: Biochemistry and Molecular Biology Research Unit, Dasman Diabetes Institute, Kuwait City, Kuwait. Electronic address: ali.tiss@dasmaninstitute.org.
authors: Ali
authors: A
authors: Tiss
mesh_terms: D016475:3T3 Cells; D000328:Adult; D015308:Anaerobic Threshold; D000818:Animals; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015444:Exercise; D005260:Female; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D015398:Signal Transduction; D050151:Subcutaneous Fat / Q000378:metabolism; D056811:Unfolded Protein Response / Q000235:genetics; D055105:Waist Circumference
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D002097:C-Reactive Protein
keywords: Adipose tissue; ER stress; GRP78; Obesity; Physical exercise