AG&M annual report 2018

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AG&M Science Impressions 2018 The gut-brain axis in obesity Richard IJzerman and Madelief Wijdeveld The pathophysiological pathways that influence the CNS regulation of food intake are the focus of Richard IJzerman’s research group. Obesity is a major public health problem due to its pandemic occurrence and its association with adverse consequences. Comparable to the role of CNS reward and satiety responses in drug addiction, we and others have demonstrated that obese individuals are characterized by excessive eating due to altered central nervous system (CNS) reward and satiety responses to food. To regulate food intake, signals arising from peripheral organs involved in food intake, digestion and storage, such as the gut, pancreas, and adipose tissue, convey information on hunger and/or satiety to the CNS. The ability of the gut to communicate with the CNS is known as the gut–brain axis. Hormonal gut-brain axis Glucagon like peptide (GLP)-1 receptor agonists showed positive results with regard to weight reduction in humans. Previous studies have demonstrated that gutderived GLP-1 is important in the regulation of feeding by relaying meal-related information on nutritional status to the brain. In order to study its specific effects on neuronal activity in the brain, our group performed various functional MRI studies where people were exposed to both virtual and actual food stimuli. Various studies performed by our group have demonstrated that blocking the action of endogenous GLP-1 prevented meal induced reductions in CNS activation in obese T2DM patients. We also demonstrated by using fMRI that GLP-1 receptor activation (using a GLP-1 receptor agonist) acutely decreased food intake and also decreased brain responses to visual food cues, which may reduce food craving. In addition, GLP-1 receptor activation acutely increased responses to actual food intake, which may prevent overeating. After short term treatment, patients using a GLP-1 receptor agonist also showed decreased responses to food pictures. Unfortunately, the CNS effects of the GLP-1 receptor agonist disappeared after 12 weeks, and weight loss with GLP-1 receptor agonists is on average only 3 kg. Thus, in order to develop more powerful preventive and therapeutic strategies, it is important to gain further insight into pathways that influence central reward and satiety circuits in the context of obesity. Metabolic gut-brain axis The last two decades have produced an avalanche of studies revealing that intestinal microbiota provide a substantial metabolic and physiological contribution to energy homeostasis in the host. Obesity has been associated with alterations in composition of intestinal microbiota, and transfer of “obese” microbiota can induce adiposity and hyperphagia in animals, suggesting that gut microbiota may influence host feeding behavior. The mechanisms underlying effects of intestinal bacteria on host appetite in animal studies are unknown, but may involve effects of short chain fatty acids (SCFAs), in particular acetate. Acetate may be an important player in the gut-brain axis. Acetate is produced when non-digestible carbohydrates undergo fermentation by the colonic microbiota. High amounts of acetate reach the peripheral circulation and can also directly affect host metabolism and function. Acetate crosses the blood–brain barrier in rodents, but the effects of acetate on food intake in animals are controversial. In humans, acetate has been shown to cross the blood–brain barrier and can be used as a substrate in the brain. In addition, there is some evidence that acetate increases short-term subjective ratings of satiety and reduces body weight in humans. In collaboration with Max Nieuwdorp, PhD student Madelief Wijdeveld investigates the interaction between the SCFA acetate and brain circuits involved in the regulation of food intake in humans. Madelief 28
AG&M Science Impressions 2018 Richard IJzerman and Madelief Wijdeveld applied and got selected for the Amsterdam UMC MD/ PhD Scholarship in 2018, which provides a medical student with the possibility to perform combine their clinical internships with 3 years of PhD research. We prospectively investigate the association of gut derived acetate on progression of obesity in relation to CNS responses to food stimuli after a follow-up of approximately 4 years in a population based cohort (the prospective Amsterdam HELIUS (Healthy Life in an Urban Setting) cohort). We selected the extremes, that is individuals with high and low intestinal acetate production based on the intestinal acetate converting activity. In these selected individuals we measure insulin responses upon a standardized mixed meal as well as CNS responses to food related stimuli (fMRI), BMI and weight gain in the following 4 years. Data collection is almost finished. In a new project, we will study the effects of direct acetate infusion into the peripheral circulation on CNS responses to food stimuli in obese and lean humans. Conclusion Insight into the pathophysiological pathways that lead to obesity may provide new therapeutic targets. Because acetate and other gut derived factors can easily be manipulated, the results from our studies may offer a tractable approach to improve activity in brain circuits involved in the development of obesity. MD/PhD talent grant AMC 2018 Madelief Wijdeveld. Role of intestinal acetate in human food intake and insulin secretion. Universiteit van Nederland. NWO. Waarom is dik worden zo makkelijk? https://youtu.be/dC4BAJV_7U4 29
Page 1 and 2: Amsterdam Gastroenterology and Meta
Page 3 and 4: Contents The mission and vision of
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