title: Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss.
abstract: OBJECTIVE
  Obesity is associated with insulin resistance and type 2 diabetes, although the mechanisms linking these pathologies remain undetermined. Recent studies in rodent models revealed endoplasmic reticulum (ER) stress in adipose and liver tissues and demonstrated that ER stress could cause insulin resistance. Therefore, we tested whether these stress pathways were also present in obese human subjects and/or regulated by weight loss.
  
  
  METHODS
  Eleven obese men and women (BMI 51.3 +/- 3.0 kg/m2) were studied before and 1 year after gastric bypass (GBP) surgery. We examined systemic insulin sensitivity using hyperinsulinemic-euglycemic clamp studies before and after surgery and collected subcutaneous adipose and liver tissues to examine ER stress markers.
  
  
  RESULTS
  Subjects lost 39 +/- 9% body wt at 1 year after GBP surgery (P < 0.001), which was associated with a marked improvement in hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Markers of ER stress in adipose tissue significantly decreased with weight loss. Specifically, glucose-regulated protein 78 (Grp78) and spliced X-box binding protein-1 (sXBP-1) mRNA levels were reduced, as were phosphorylated elongation initiation factor 2alpha (eIF2alpha) and stress kinase c-Jun NH2-terminal kinase 1 (JNK1) (all P values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2alpha before surgery, which was reduced in post-GBP sections.
  
  
  CONCLUSIONS
  This study presents important evidence that ER stress pathways are present in selected tissues of obese humans and that these signals are regulated by marked weight loss and metabolic improvement. Hence, this suggests the possibility of a relationship between obesity-related ER stress and metabolic dysfunction in obese humans.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Gregor
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Elisa
authors.initials: E
authors.lastname: Fabbrini
authors.forename: B Selma
authors.initials: BS
authors.lastname: Mohammed
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Eagon
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: Samuel
authors.initials: S
authors.lastname: Klein
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005500:Follow-Up Studies; D015390:Gastric Bypass; D015309:Glucose Clamp Technique; D006801:Humans; D006946:Hyperinsulinism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000502:physiology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000502:physiology; D009765:Obesity / Q000503:physiopathology* / Q000601:surgery; D013312:Stress, Physiological