Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats

Bethany P Cummings,Frederik Hansen,Jaehyoung Kim,Fangrui Ma,Ahmed Bettaieb,Mark Kowala,Michael L Chouinard,Fawaz G Haj,Noreene Shibata,James L Graham,Peter J Havel,Jacob Jelsing,Cecilia Giulivi,Niels Vrang,Kimber L Stanhope

doi:10.1242/dmm.010421

Abstract

SUMMARYPost-operative increases in circulating bile acids have been suggested to contribute to the metabolic benefits of bariatric surgery; however, their mechanistic contributions remain undefined. We have previously reported that ileal interposition (IT) surgery delays the onset of type 2 diabetes in UCD-T2DM rats and increases circulating bile acids, independently of effects on energy intake or body weight. Therefore, we investigated potential mechanisms by which post-operative increases in circulating bile acids improve glucose homeostasis after IT surgery. IT, sham or no surgery was performed on 2-month-old weight-matched male UCD-T2DM rats. Animals underwent an oral fat tolerance test (OFTT) and serial oral glucose tolerance tests (OGTT). Tissues were collected at 1.5 and 4.5 months after surgery. Cell culture models were used to investigate interactions between bile acids and ER stress. IT-operated animals exhibited marked improvements in glucose and lipid metabolism, with concurrent increases in postprandial glucagon-like peptide-1 (GLP-1) secretion during the OFTT and OGTTs, independently of food intake and body weight. Measurement of circulating bile acid profiles revealed increases in circulating total bile acids in IT-operated animals, with a preferential increase in circulating cholic acid concentrations. Gut microbial populations were assessed as potential contributors to the increases in circulating bile acid concentrations, which revealed proportional increases in Gammaproteobacteria in IT-operated animals. Furthermore, IT surgery decreased all three sub-arms of ER stress signaling in liver, adipose and pancreas tissues. Amelioration of ER stress coincided with improved insulin signaling and preservation of β-cell mass in IT-operated animals. Incubation of hepatocyte, adipocyte and β-cell lines with cholic acid decreased ER stress. These results suggest that postoperative increases in circulating cholic acid concentration contribute to improvements in glucose homeostasis after IT surgery by ameliorating ER stress.

Highlights

Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), is currently the most effective treatment for obesity and often results in type 2 diabetes resolution and possibly type 2 diabetes prevention (Buchwald et al, 2004; Cummings et al, 2010c; Schauer et al, 2012; Sjöström et al, 2004)
After ileal interposition (IT) surgery, improvements in glucose tolerance and β-cell mass coincided with the amelioration of endoplasmic reticulum (ER) stress signaling in liver, adipose and pancreas tissues in this model, independently of body weight changes
These results suggest that increases in circulating cholic acid concentrations after IT surgery contribute to improvements in glucose metabolism by decreasing ER stress

Summary

Introduction

Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), is currently the most effective treatment for obesity and often results in type 2 diabetes resolution and possibly type 2 diabetes prevention (Buchwald et al, 2004; Cummings et al, 2010c; Schauer et al, 2012; Sjöström et al, 2004). In the role of endocrine and metabolite changes in the effects of bariatric surgery to induce weight loss and prevent diabetes onset (Scott and Batterham, 2011; Thaler and Cummings, 2009). Post-operative elevations in circulating bile acids have become an increasingly cited mechanism for the metabolic benefits of bariatric surgeries, such as RYGB and vertical sleeve gastrectomy (Cummings et al, 2012; Patti et al, 2009; Thaler and Cummings, 2009). RYGB produces several post-operative alterations in normal GI anatomy and function, such as reduction in gastric volume, bypass of the proximal small intestine and increased flux of incompletely absorbed nutrients and bile into the distal small intestine. The only major change produced by this surgery is increased flux of incompletely absorbed nutrients and bile to the distal small intestine (Strader, 2006). By investigating the effects of only one of the anatomical alterations produced by RYGB in isolation, we can better assess mechanisms by which this component of bariatric surgery improves glucose metabolism

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