title: Bile-acid-mediated decrease in endoplasmic reticulum stress: a potential contributor to the metabolic benefits of ileal interposition surgery in UCD-T2DM rats.
abstract: Post-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.
authors.affiliation: Department of Molecular Biosciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA. bpcummings@ucdavis.edu
authors.forename: Bethany P
authors.initials: BP
authors.lastname: Cummings
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bettaieb
authors.forename: James L
authors.initials: JL
authors.lastname: Graham
authors.forename: Jaehyoung
authors.initials: J
authors.lastname: Kim
authors.forename: Fangrui
authors.initials: F
authors.lastname: Ma
authors.forename: Noreene
authors.initials: N
authors.lastname: Shibata
authors.forename: Kimber L
authors.initials: KL
authors.lastname: Stanhope
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giulivi
authors.forename: Frederik
authors.initials: F
authors.lastname: Hansen
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
authors.forename: Mark
authors.initials: M
authors.lastname: Kowala
authors.forename: Michael L
authors.initials: ML
authors.lastname: Chouinard
authors.forename: Fawaz G
authors.initials: FG
authors.lastname: Haj
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002432:Cecum / Q000187:drug effects / Q000382:microbiology; D019826:Cholic Acid / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000601:surgery*; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D020563:Gammaproteobacteria / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007082:Ileum / Q000187:drug effects / Q000473:pathology* / Q000601:surgery*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001647:Bile Acids and Salts; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D019826:Cholic Acid; D005947:Glucose