Behavioural and neuroimaging studies of food reward after bariatric surgery for obesity

BACKGROUND Roux-en-Y gastric bypass (RYGB) surgery is the most effective treatment for obesity and has greater efficacy for weight loss than gastric banding (BAND) surgery. The superior weight loss seen after RYGB may result from profoundly different effects on food hedonics and reward brought about by physiological changes secondary to the distinct manipulations of gut anatomy. AIMS To compare body mass index (BMI) matched patients after RYGB or BAND surgery and unoperated controls using comprehensive phenotyping of brain structure and function, eating behaviour and metabolism. METHODS In these cross-sectional studies, un-operated controls and patients after RYGB and BAND surgery had functional and anatomical neuroimaging of food reward systems. Reward responses to food were assessed with a functional magnetic resonance imaging (fMRI) food picture evaluation task. Anatomical differences in grey and white matter were assessed using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). Eating behaviour, food appeal and palatability, potential mediators, and post-ingestive effects were compared between groups using questionnaires, test meals, food diaries and assay of plasma hormones and metabolites. Surgical patients were compared in both the fasted and fed state, and after administration of the somatostatin analogue, Octreotide, to suppress anorexigenic gut hormone responses after RYGB. RESULTS Obese patients after RYGB had healthier gut-brain-hedonic responses to food than patients after BAND surgery. RYGB patients had lower activation than BAND patients in brain reward systems, particularly to high-calorie foods, including the orbitofrontal cortex, amygdala, caudate nucleus, nucleus accumbens and hippocampus. This was associated with lower palatability and appeal of high-calorie foods, and healthier eating behaviour, including less fat intake, in RYGB compared to BAND patients and/or BMI-matched unoperated controls. These differences were not explicable by differences in hunger or psychological traits between the surgical groups, or by differences in brain structure as measured by VBM and DTI. However anorexigenic plasma gut hormones (GLP-1 and PYY), plasma bile acids and symptoms of dumping syndrome were increased in RYGB patients. Octreotide increased nucleus accumbens activation to food pictures, increased food appeal and decreased post-meal satiety in patients after RYGB, but not BAND surgery. The preliminary nature of this small study precludes extensive interpretation especially of the difference between surgical groups. Patients in the operated groups (RYGB and BAND) had lower grey matter density in areas involved in reward processing, including the amygdala, nucleus accumbens and hippocampus compared to BMI-matched controls. There was no difference between the groups in white matter tract integrity. CONCLUSIONS Identification of these differences in the gut-brain axis and hence food hedonic responses as a result of altered gut anatomy/physiology provides a novel explanation for the more favorable long-term weight loss seen after RYGB than BAND surgery. This supports targeting of gut-brain reward systems for future treatments of obesity.Open Acces

Feeling full and being full : how gastric content relates to appetite, food properties and neural activation

Aim: This thesis aimed to further determine how gastric content relates to subjective experiences regarding appetite, how this relation is affected by food properties and whether this is visible in neural activation changes. Method: This was studied using questionnaires, MRI of the stomach and fMRI of the brain. Randomized, controlled crossover experiments with healthy men and for one experiment women were performed. Results: MRI measurements of the stomach as opposed to an indirect measurement by proxy, such as 13C breath testing are to be preferred. We show that gastric emptying is affected by energy load, and to a much smaller extent by viscosity. Additionally we show that a thick shake containing 100 kcal will yield higher fullness sensations than a thin shake containing 500 kcal. In the chapter we name this phenomenon ‘phantom fullness’, i.e., a sense of fullness and satiation caused by the taste and mouthfeel of a food which is irrespective of actual stomach fullness. A liquid meal followed by a drink of water empties about twice as fast in the first 35 minutes compared to the same amount of water incorporated within the liquid meal. Using MRI we were able to show layering within the stomach and increased emptying of this watery layer. With 300mL of increased gastric content inducing distention, appetite was lowered. Ingestion led to significant changes in activation in the right insula and parts of the left and right inferior frontal cortices over time. Women retain significantly more fluid after a carbonated drink in their stomach than men. When comparing correlations between subjective ratings and intragastric liquid and gas and total gastric volume, nausea and fullness correlated strongest with the liquid fraction within the stomach, bloating strongest with total gastric volume. Conclusion: There are marked differences betweengastric content and subjective experiences regarding appetite. Viscosity is a main driver of these differences. Combined gastric MRI and brain fMRI measurements need to be performed to understand this further.</p

Understanding the mechanisms of G protein-coupled receptor mediated nutrient sensing in enteroendocrine cells

Nutrient sensing is the process by which cells detect and respond to dynamic metabolite fluctuations. In gastrointestinal enteroendocrine cells (EECs), this process facilitates the post-prandial secretion of anorectic gut hormones. As these elicit diverse impacts on physiology, appetite and metabolism, they present potential targets for anti-obesity therapeutics. Short chain fatty acids (SCFAs) are produced as by-products of the fermentation of non-digestible carbohydrates by the gut microbiota, predominantly in the colon. SCFAs induce EECs to release anorectic hormones GLP-1 and PYY by acting as ligands at G protein-coupled receptors (GPCRs) FFAR2 and FFAR3. Thus far, it has been confirmed that FFAR2 and FFAR3 couple to Gαi/o but FFAR2 alone activates Gαq/11 calcium mobilisation. However, FFAR2 is seemingly only able to induce calcium signals in EECs when activated by synthetic FFAR2 ligands, not SCFAs. It is plausible that crosstalk between FFAR2 and FFAR3 could be preventing FFAR2 coupling to Gαq in response to SCFAs. This has been assessed by combining genome editing and functional signalling assays. Conversely, the results demonstrate that co-expression of FFAR2 and FFAR3 in heterologous systems enhances propionate-mediated calcium mobilisation. Futhermore, functional knockout of FFAR3 has no impact on propionate signalling in EECs. Interestingly, crosstalk with FFAR4 may represent a mechanism for the lack of SCFA-induced Gαq signalling in EECs. The impact of SCFAs on the expression of other GPCR signalling machinery remains poorly characterised. This project has, to date, demonstrated propionate and butyrate robustly upregulate transcripts encoding the umami taste receptor, via a Gαi/o independent mechanism. We show that overnight exposure of EECs to butyrate enhances the calcium mobilisation in response to L-Alanine when IMP is present. Therefore, I propose an alternative, indirect mechanism by which SCFAs enhance gut hormone release; namely, by inducing a hypersensitivity of EECs to L-amino acids by promoting expression of taste signalling components.Open Acces