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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/m^sup 2^) 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 2a (eIF2α) and stress kinase c-Jun NH^sub 2^-terminal kinase 1 (JNKl) (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. Diabetes 58:693-700, 2009
Increased adiposity is associated with a group of chronic metabolic disorders, including insulin resis- tance, type 2 diabetes, and nonalcoholic fatty liver disease (1). The prevalence of this cluster of abnor- malities has increased significantly in the past few decades following the marked rise of obesity worldwide (2,3). The mechanisms responsible for the emergence of these disorders have been an intense area of investigation. In the past decade, it was recognized and established that chronic inflammatory and stress responses are a central feature of obesity, insulin resistance, and type 2 diabetes and contribute to the metabolic imbalance (4). However, the pathways and mechanisms giving rise to the chronic inflammatory...