Nutrient modulation of vagal afferent signalling

The way that food intake is controlled is attracting intense interest. An understanding of these systems is required for the treatment of obesity which is now widely recognised as a major threat to health. Many different factors are thought to contribute to the obesity epidemic including genetic factors and changes in life style and diet. While the importance to health of interactions between nutritional factors and genes is widely appreciated and often discussed, these interactions nevertheless remain poorly understood. The present application is based on recent findings that indicate new mechanisms linking the sensing of nutrients in the wall of the gut to changes in the expression of genes encoding proteins associated with control of food intake. Recent work suggests that following a meal, the ingested food triggers several different signals that converge to act on a nervous pathway, the so called vagal afferent neurones, that link the gastrointestinal tract to the brain. Interactions between these signals are more extensive than hitherto thought, and are likely to be relevant both to control of food intake, and to how it is digested. Recent observations also suggest a new type of control mechanism operating at the level of vagal afferent neurones. In particular, it appears that patterns of food intake over a period of 24 hr or more may determine the presence or absence of key molecules, receptors, that recognise signalling molecules regulating how much we eat. These changes are thought to reflect different activities of the genes that encode a receptor for cannabinoids (known as the CB-1 receptor) that is known to be involved in control of appetite. The overall objective of the proposed studies is to characterise changes in expression of genes encoding key components of the vagal signalling pathway in a way that can inform human studies. Specifically, the proposed studies will define how nutrients change gene expression in vagal afferent neurons, will establish the significance for the control of digestion and feeding in humans, and will explore the role of genetic differences between people in accounting for different responses to nutrients.

Signals from the gut to the CNS regulate food intake and digestion. Modulation of these signals, through gastric surgery, is an effective treatment for obesity. Our work has focused on cholecystokinin (CCK) which is released by dietary fat and protein and regulates their digestion by matching secretion of pancreatic enzymes and bile salts to the delivery of nutrient to the small intestine. The latter is achieved by inhibition of gastric emptying and food intake through actions mediated by vagal afferent neurones. Our recent work suggests these neurones also express receptors for neurohumoral agents stimulating food intake, notably receptors for orexin (Ox-1), ghrelin (GHS-1), melanin concentrating hormone (MCH-1) and cannabinoids (CB-1). Expression of the CB-1 and MCH-1 receptors is increased during fasting and down-regulated by CCK, suggesting that signalling via vagal afferent neurones might be modulated depending on previous nutritional intake, and raising the possibility of a novel mechanism influencing autonomic responses and food intake. The central questions addressed in the present proposals are how do vagal afferent neurones integrate gastrointestinal signals and in turn influence digestive function, eating behaviour and satiety, what is the role of nutrient-regulated gene expression in these processes and what mechanisms account for the variability between individuals? We propose (a) in an animal model, to characterise the changes in receptor expression in vagal neurones that are dependent on feeding, (b) in human studies, to determine the importance of interactions between CCK-1 and CB-1 receptor signalling for control of nutrient delivery to the small intestine, (c) to explore the extent to which individual variation in responses to endogenous CCK might be attributable to single nucleotide polymorphisms. Together the results should lead to new understanding of the mechanisms by which nutrient intake and digestion is modulated in man.