Jejunal ketogenesis as a fat sensor – a novel intestinal mechanism in glycemic control with diabetes in sight
Description: All comorbidities to obesity, particularly type 2 diabetes (T2D) are counteracted by Roux-en-Y gastric bypass (RYGB). We use RYGB as a human model to identify mechanisms linking obesity with T2D. Recently, we discovered jejunal ketogenesis as a candidate. Individuals with obesity showed high production of the ketone body β-hydroxybutyric acid (βHB) in the jejunum, and it was increased in normal weight humans by high-fat diet. After RYGB, βHB and its rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase were decreased. βHB inhibited the incretin hormone GLP-1 in vitro in enteroendocrine cells. Therefore, our hypothesis is that βHB acts as a "sensor" for fat, and prolonged high-fat diet can inhibit incretins. We propose the following studies; 1) βHB-effects on incretin hormones in human enteroids, i. e. cultured jejunal mucosa (planned for 2023-2025).2) RCTs in patients with obesity and T2D with focus on incretins, glycemic control and metabolomics when treated with: A./ high-fat vs. high-carb diet (2023-2025) B./ perorally given βHB encapsulated for release in the upper vs. distal intestine (2024-2025)3) Biopsies from different parts of the intestine before and after RYGB analyzed for global proteomics and microbiota to examine their effect on ketones and incretins (2023-2025).The aim is to identify mechanisms for T2D and new drugable targets for treatment of obesity and T2D.
Funder: Vetenskapsrådet
Amount: SEK 3,600,000
Funding type: research
Funder scheme: Project grant
Start date: 2024-01-01
End date: 2026-12-31
Investigator: Ville Wallenius
Institution: University of Gothenburg
Funded outputs count: 2
Funder award ID: 2023-02357
OpenAlex ID: G8348058263