Objective Food intake normally stimulates release of satiety and insulin-stimulating intestinal hormones, such as glucagon-like peptide (GLP)-1. This response is blunted in obese insulin resistant subjects, but is rapidly restored following Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised this to be a result of the metabolic changes taking place in the small intestinal mucosa following the anatomical rearrangement after RYGB surgery, and aimed at identifying such mechanisms.
Design Jejunal mucosa biopsies from patients undergoing RYGB surgery were retrieved before and after very-low calorie diet, at time of surgery and 6 months postoperatively. Samples were analysed by global protein expression analysis and Western blotting. Biological functionality of these findings was explored in mice and enteroendocrine cells (EECs) primary mouse jejunal cell cultures.
Results The most prominent change found after RYGB was decreased jejunal expression of the rate-limiting ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGCS), corroborated by decreased ketone body levels. In mice, prolonged high-fat feeding induced the expression of mHMGCS and functional ketogenesis in jejunum. The effect of ketone bodies on gut peptide secretion in EECs showed a ∼40% inhibition of GLP-1 release compared with baseline.
Conclusion Intestinal ketogenesis is induced by high-fat diet and inhibited by RYGB surgery. In cell culture, ketone bodies inhibited GLP-1 release from EECs. Thus, we suggest that this may be a mechanism by which RYGB can remove the inhibitory effect of ketone bodies on EECs, thereby restituting the responsiveness of EECs resulting in increased meal-stimulated levels of GLP-1 after surgery.
- obesity surgery
- glucagen-like peptides
- small bowel
- diabetes mellitus
- enterocyte biology
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Contributors Study concept and design: VW, LF, ES, AC, EElias. Acquisition of data: VW, EElias, BH, AC, PL, FR, FMG. Analysis and interpretation of data: VW, EElias, EElebring, BH, PL, FR, CLR, ND, FMG, LF. Drafting of the manuscript: VW, EElebring, LF. Critical revision of the manuscript: AC, EElias, PL, FR, CLR, ND, FMG. Statistical analysis: VW, EElias, EElebring, BH, PL, FR, FMG.
Funding This study was funded by the following grants: ALFGBG-673931 from the Western Region of Sweden, grants from Erik and Lily Philipson memorial foundation, MRC [MRC_MC_UU_12012/3 and MRC_MC_UU_12012/5], Wellcome Trust [106262/Z/14/Z, 106263/Z/14/Z, 100574/Z/12/Z].
Competing interests VW reports grants from Western Region of Sweden, grants from Erik and Lily Philipson memorial foundation. FMG is a paid consultant for Kallyope, New York. The Gribble-Reimann lab hosts projects which receive funding from Medimmune/AstraZeneca (FMG/FR). CLR reports research grants from Science Foundation Ireland, and the Health Research Board, Ireland, during the conduct of the study; other from Novo Nordisk, other from GI Dynamics, personal fees from Eli Lilly, grants and personal fees from Johnson and Johnson, personal fees from Sanofi Aventis, personal fees from Astra Zeneca, personal fees from Janssen, personal fees from Bristol-Myers Squibb, personal fees from Boehringer-Ingelheim outside of the submitted work.
Patient consent for publication Obtained
Ethics approval This study was approved by the Regional Ethics Review Board of Gothenburg, approval numbers 193–02, 647–05 and 007–09, and performed in accordance with the Declaration of Helsinki. All animal procedures were approved by the animal ethics committee of the University of Gothenburg, approval numbers 90–2007 and 246–2009, or according toUK Home Office project license 70/7824 and local regulations (Animals (Scientific Procedures) Act 1986 Amendment Regulations SI 2012/3039).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.