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.

Research Design and 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 weight 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, Grp78 and spliced XBP-1 mRNA levels were reduced, as were phosphorylated eIF2α and stress kinase JNK1 (all p values <0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2α 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.