Zakeri, Roxanna;
(2022)
Precision bariatric surgery: Targeting the ghrelin system to optimise health outcomes.
Doctoral thesis (Ph.D), UCL (University College London).
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Roxanna Zakeri - PhD thesis - Redacted.pdf - Other Access restricted to UCL open access staff until 1 August 2025. Download (6MB) |
Abstract
Bariatric surgery is the most effective treatment available for severe obesity, producing significant and durable weight loss, however response varies widely. One in five patients do not reach therapeutic weight loss targets. The underlying mechanisms are unclear but mounting evidence implicates a differential gut hormone response. This thesis investigates the role of the gastric-derived orexigenic hormone, ghrelin, in mediating weight loss after bariatric surgery. An association between pre-operative plasma acyl-ghrelin concentration and percentage weight loss was revealed at 6-weeks after primary sleeve gastrectomy (SG), which paralleled significant reduction in subjective ratings for appetitive drive. Bioimpedance analysis and magnetic resonance imaging revealed significant decreases in lean mass and body fat, including visceral, subcutaneous and ectopic fat, at 6-weeks post-surgery which correlated with post-operative change in fasting plasma acyl- and desacyl-ghrelin concentration. A cohort of patients with suboptimal weight loss beyond 1-year post-surgery with no identifiable surgical, medical or psychological cause were studied. Aberrant circulating ghrelin profile was revealed in 83.3%, with the prevalence twice as high after Roux-en-Y gastric bypass (RYGB) than SG. RYGB patients exhibited higher fasting and postprandial circulating ghrelin concentrations but retained a greater ability for postprandial acyl-ghrelin suppression. In a proof-of-concept, double-blind, randomised placebo-controlled mechanistic trial in this patient cohort, pharmacological inhibition of ghrelin o-acyltransferase (GOAT) – the enzyme that acylates ghrelin thus enabling receptor binding – reduced circulating acyl-ghrelin concentration by 58.9% and increased desacyl-ghrelin by 29.3% within 7 days. Importantly, acyl-ghrelin : desacyl-ghrelin ratio reduced to well below the 10% threshold for aberrancy. Clinically significant reductions in subjective markers of homeostatic and hedonic appetite were identified, but no change in ad libitum or free-living energy intake. Striking improvements in circulating lipid profile were observed that support preclinical reports of ghrelin’s role in regulating lipid metabolism. Taken together, these findings suggest that detailed phenotyping of people with obesity according to circulating ghrelin profile, and targeting multimodal therapeutic strategies to reduce ghrelin signalling, could help to improve weight loss and health outcomes.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Precision bariatric surgery: Targeting the ghrelin system to optimise health outcomes |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) Licence (https://creativecommons.org/licenses/by-nc-nd/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Bariatric surgery, Obesity, Ghrelin, Appetite |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151310 |
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