My name is Birgitte Holst, and I am a Professor at University of Copenhagen with specialty in Molecular and Metabolic Pharmacology. This is a research field that covers research in the molecular mechanisms of pharmacological treatment approaches for obesity and diabetes. In this lecture I will primarily focus on an update on the current and novel approaches used to develop drugs in the treatment of obesity. I will start with an update on the physiological regulation of appetite and satiety in relation to meals. Then I will continue with a short overview of the previous and current treatment on the market for the treatment of obesity and finally I will describe some of the promising novel approaches pursued for future treatment. Physiological regulation of appetite and satiety: The normal physiological regulation of hunger is complex, in particular in humans, and consists of many known and unknown factors. However, it is well accepted that before a meal the plasma levels of so-called satiety hormones are low and after ingestion of a meal the plasma levels increases. These satiety hormones are typically gastrointestinal derived hormones. Some of the satiety hormones that increases are Glucagon like peptide 1 (GLP-1) and Peptide YY (PYY) some of these are peptide hormones secreted from the small and large intestine in response to food items both carbohydrate, fat and proteins. In contrast, the most well studied hunger inducing hormone - ghrelin - does the opposite and decreases in response to meal ingestion. Importantly, ghrelin is secreted mainly from the stomach After ingestion of a meal the food will be de cleaved down to minor components that will be absorbed to provide fuel for the body. As shown on this slide, the lipids are cleaved down to long chained free fatty acids (LCFA) and monoacylglycerol (MG). Proteins are cleaved down to smaller peptides by proteinases and carbohydrates are cleaved down to monosaccharide or disaccharids by different enzymes. Other carbohydrates like fibers are metabolized by the gut microbiota to short chain fatty acids (SCFA), which may provide minor amount of energy. Most importantly the fibers are important for the motility of the gut. However, and highly important for the appetite regulation, these minor components of the food, also act as signaling molecules on the entero-endocrine cells - depicted here in green. The entero endocrine cells carries receptors - so called nutrient sensors - for the nutrient signaling molecules. An important class of these receptors is the 7TM receptor class that is well known as important drug targets. When the entero-endocrine cell becomes activated through these receptors they release- the satiety inducing hormons and transmitters. Some of these were also mentioned in the previous slide such as GLP-1 and PYY - but there are many more. The released transmitters or hormones may act either as paracrine factors on the surrounding cells and modulate for example the function of the enterocyte. They may also stimulate the enteric neurons and modulate motility or they may stimulate the vagal afferent and transmit signals to the brain. Finally, they may also act as actual hormones through the blood stream. Many different entero-endocrine cells exist and the composition of hormones they release in response to a meal varies depending on the cell type. These entero-endocrine cells may be important novel drug targets for treatment of obesity but also diabetes. The reason why the entero-endocrine cells are such attractive drug targets is that stimulation of this cell type gives rise to an almost physiological satiety feeling - not only as result of release of a single hormone but through release of a package of hormones in one message. For example, when you stimulate the entero-endocrine cells, called L-cells, by a nutrient, the L-cells will release a package of hormones consisting of GLP-1, GLP-2 and PYY. These will deliver the "message" - stop eating slow down gastric emptying prepare the endocrine pancreas regenerate the intestinal cells and potentially other functions Data suggest that the amount of hormones released is dependent on the load of nutrition. For examples it has been observed that a small meal of few Kcal -induces a weak increase in PYY secretion. A larger meal gives a higher PYY secretion and finally a huge meal of 4500 Kcal -almost corresponding to the daily energy need for an adult man - will further increase the PYY secretion. This shows that the entero-endocrine cells have a residual capacity to secrete more satiety hormones than required for a normal meal. When using the entero-endocrine cells as drug targets the hypothesis is that a drug that artificially stimulates the receptors for the nutrient will induce a "feeling like" ingesting a huge meal even when only small amount of Kcals are ingested. The hormones and transmitters secreted from the gut many serve many different functions. The satiety hormones such as GLP-1 and PYY, may exert most of their appetite decreasing effect through the brain. But they also act directly on the GI tract, modulating the motility and secretion. Some hormones - the incretin hormones GLP-1 and GIP - are important for insulin secretion in the endocrine pancreas, hence regulating the glucose metabolism. Finally, some of the hormones will act on other peripheral tissue such as bone, skeletal muscles and the adipocytes. Satiety is mainly mediated through the brain. Increased secretion of hormones like GLP-1 and PYY act as hormones through the blood stream and communicate with the brain. Decreased secretion of the hunger inducing hormone -ghrelin - is also perceived by the brain - this is mediated either as a hormonal action through the blood or through the vagal nerve. Likewise, cholecystokinin - CCK -is secreted from the upper GI tract in response primarily to fat and protein rich food items. CCK is important for secretion of bile acid and digestive enzymes from the pancreas. However, it is also an important satiety hormone whose effect is mediated mainly through the vagal nerve. In addition to the satiety signaling from the GI tract derived hormones, also other factors are important such as insulin from the pancreas and leptin from the adipose tissue also regulate the appetite and act as satiety signals on the brain. In the brain, the hypothalamus is the main region responsible for appetite regulation and for sensing the nutritional status of the periphery. In the hypothalamus two populations of neurons are highly important for sensing of the peripheral energy status - the NPY/AgRP neurons (shown in green)and the POMC neurons (shown in red). Activation of the NPY/AgRP neurons increases the synaptic secretion of AgRP, which in turn inhibits the stimulatory MC4 receptors in the paraventricular nucleus (PVN). It further induces section of NPY that activates the inhibitory receptors Y1/5 receptors also in PVN. The net result is an increase in appetite. In contrast, the activation of the POMC neurons induces secretion of a-MSH which activates the MC4 receptors in PVN. Activation of this population of neurons in the PVN will lead to increased metabolic rate and decreased appetite. For example by activation of the thyroid releasing hormone (TRH) producing neurons, that will increase the thyroid axis. In the periphery, the size of the body fat stores is sensed by leptin - high amount of fat result in high plasma levels of leptin. The glycemic status, however, is sensed by insulin. Both of these peripheral hormones decrease appetite and increase metabolic rate - both by inhibition of the stimulatory NPY/AgRP neurons and by activation of the inhibitory POMC neurons. Both GLP-1 and PYY3-36 from the GI tract, both decrease appetite and act through different populations of neurons. GLP-1 acts on and activates the POMC neurons whereas PYY inhibits the NPY/AgRP neurons. Finally, the hunger hormone, ghrelin, activates the NPY/AgRP neurons and indirectly inhibits the POMC neurons - thereby increasing food intake. After food intake the secretion of this hormon is decreased. So in summary: Nutrient sensors located on the entero-endocrine cells are activated by food component - Free fatty acids and monoacylglycerol - Small Peptides - Monosaccharaides Activation of the entero-endocrine cells will lead to secretion of : - Satiety hormones such as GLP-1, PYY and CCK The satiety hormones regulate: - appetite and energy expenditure - motility of the gut - function of the enterocytes - secretion from the pancreas - endocrine and exocrine This was some background on some important factors in the satiety and appetite regulation under normal physiological condition. It was not an exhaustive description - but an overview of the GI tract based satiety signals that can be considered basis for some aspects of future drug development.