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 menand women (BMI 51.3 Ϯ 3.0 kg/m 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 Ϯ 9% body wt at 1 year after GBP surgery (P Ͻ 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 2␣ (eIF2␣) and stress kinase c-Jun NH 2 -terminal kinase 1 (JNK1) (all P values Ͻ0.05). Liver sections from a subset of subjects showed intense staining for Grp78 and phosphorylated eIF2␣ 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

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

“…However, further studies focused in the activation or subcellular location of ATF6 would be necessary to discard the activation of ATF6 branch in the vasculature of patients with DM. During ER stress, IRE1α and PERK‐ATF4 trigger the activation of JNK, a key inflammatory signaling pathway 43, 44, 45. Interestingly, we have previously reported an enhanced activation of JNK in patients with DM, that contributes to reduced nitric oxide production and lower flow‐mediated dilatation 30.…”

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…The expansion of ISCs in Xbp1 /(IEC) mice, and the desire to delineate the specific tumor-promoting role of Xbp1 deficiency specifically in IECs, prompted us to Epithelial Xbp1 suppresses tumor formation in Apc min/+ mice Inflammatory signaling is an important contributor to CAC but also to sporadic and familial CRC (Rakoff-Nahoum and Medzhitov, 2007; Lee et al, 2010), with overlapping and distinct inflammatory pathways being involved (Salcedo et al, 2010). ER stress in various organs, including the liver, skeletal muscle, adipose tissue (Ozcan et al, 2004;Gregor et al, 2009;Kars et al, 2010), and intestinal crypts (Hodin et al, 2011), is associated with obesity, which is epidemiologically closely associated with increased cancer incidence, most notably CRC (Calle et al, 2003). CRC and CAC exhibit distinguishing features with regard to their molecular genetic underpinning; ;Apc min mice allowed crypt-specific stratification of Olfm4 + cell enumeration in lysozyme + and lysozyme  crypts (n = 4/4; two-sided Student's t test).…”

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