Gut-brain mechanisms mediating the effect of bariatric surgery on food reward

Calorie-dense foods induce a positive reward signal in the brain. Dopamine is an essential neurotransmitter for reward signaling, motivation and execution of goal-directed behaviors. Studies have reported a decreased expression of dopamine D2 receptors in the brain of patients with obesity (Wang et al., 2001), whereas those receptors are upregulated after bariatric surgery (van der Zwaal et al.,2016). Intriguingly, dopamine also has peripheral effects on the gut and the pancreas such as inhibition of insulin secretion which could influence the development of type 2 diabetes (T2D), one of the major comorbidities of obesity. The relationship between central dopamine signaling and development of T2D, however, has not been assessed until now. In addition, the endocannabinoid system (ECS) has also emerged as a key regulator of food intake. ECS compounds are strategically localized at every level of the brain-gut axisto exert an energy-stowing function. In the brain, both endocannabinoids and their receptor (CB1R) are localized in homeostatic and reward regions, where they act as presynaptic modulator of neurotransmitter release, including dopamine. The LaBGAS group previously showed that CB1R availability in homeostatic and reward areas is differently linked to body mass index (BMI) in healthy subjects versus patients with various food intake disorders, including obesity (Weltens etal., 2016). It remains unknown, however, whether changes in CB1R availability area predisposing factor for, or the consequence of, aberrant BMI, and what the underlying gut-brain mechanisms are of this CB1R – BMI relationship. Specifically, differences in CB1R availability have never been linked to circulating endocannabinoid levels, although it is believed that the decreased central CB1R expression in obesity results from an overactive ECS. Further, as endocannabinoids are thought to actin tandem with metabolic hormones regulating hunger and satiety, the interplay between these hormone levels and the changes in cerebral CB1R availability should also be investigated. The major aim of the present PhD project is to study the role of endocannabinoid and dopamine signaling in relation to metabolic health before and after weight loss, by identifying the neurochemical and hormonal gut-brain signaling mechanisms underlying the changes in body weight and eating behaviour after bariatric surgery.

This translates into 3 research objectives:

● Study regional CB1R availability in obesity and after bariatric surgery

● Study peripheral changes indopamine and endocannabinoid signaling in obesity and after bariatric surgery

● Investigate the relations between endocannabiniod and dopamine signaling, food intake, metabolic hormones, and glucose homeostasis in obesity and after bariatric surgery