1798 delicately regulated by various signals originating from the stomach and gut. Along the GI tract, several receptor types are present that respond to nutrients and their immediate breakdown products, such as amino acids, small peptides, fatty acids or carbohydrates (51). Increasing evidence suggests that metabolites formed by bacteria or host cells within the GI tract are also involved in this sensing process (51). Receptors are located on so-called entero-endocrine cells (EECs) and on afferent nerve terminals (see also Fig. 1). By their shape and location, these entero-endocrine cells are well equipped to sense chemical structures in the lumen and to pass their information to small blood vessel and nerve terminals. Their apical side is in contact with the luminal contents, and their basolateral side is in contact with the vasculature of the lamina propria, neural cells, and with distant enterocytes. Remarkably, several entero-endocrine cell types throughout the gut also express taste receptors, including T1R2/3 sweet taste receptors, T2R-family bitter receptors, and the taste-specific G protein Gα-gustducin (57,58). An important finding has been that taste-like nutrient sensing is necessary for normal GLP-1 secretion. Expression of sweet taste receptors was also found to be decreased in diabetic subjects with elevated blood glucose concentration (58). In addition, endocannabinoids induce sweet taste (59). This suggests that intestinal “taste” signaling is under dynamic metabolic and luminal control. Nutrient signaling to the brain is a combination of endocrine and neural processes. Vagal afferent nerve fibers are forming the enteric nervous system, which communi- cates to the brain via the N. Vagus. Nerve terminals in the mucosa contain specific receptors that recognize satiation peptides and nutrient-derived mediators (60). Upon stimulation, several satiation-inducing peptides are being released by entero-endocrine cells, including chole- cystokinin (CCK), bombesin, glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, apolipoprotein A-IV, amylin, somatostatin, enterostatin, and peptide YY (PYY). Increas- ing evidence suggests that the development of satiation cannot be simply attributed to stimulation of specific receptors at defined locations. Instead, digestion, passage through the GI tract and satiation are acting in a cascade of events. Sensing and feedback occur via signals from multiple sites in the GI system, including the stomach, proximal small intestine, distal small intestine, colon, and pancreas (52,54). Satiation signals also interact with adiposity signals, in which leptin plays an important role. The central integra- tion and control occurs by the hypothalamus, which is continuously informed about the nutritional, energetic and environmental status of the body. This complexity in signaling and cross-talk has often limited the clinical result of a single target drug, i.e. a molecule specifically acting on one receptor. Witkamp Intestinal, Pancreatic and Peripheral Receptors and Local Feed-Back Mechanisms as Potential Targets for Satiation Considering the abundance and diversity of nutrient- sensing receptors, it is understandable that they are receiving considerable interest as potential targets for satiety induction. This is also obvious from the high activity in the patent literature. Many GI receptors still have an orphan receptor status, but considerable progress is being made with their de-orphanization and characterization. The gut contains several types of receptors, for example G- protein gustducin and G-protein-coupled receptors (includ- ing GPR119, 93, 55,120 and 40), TRPV type 1, and various other types including melanocortin, opioid and PPAR (51,58,61–66). So far, intensive research for phar- macological ligands that possess significant effects on body weight has not led to important breakthroughs. An interesting exception to this seems to be the G-protein- coupled receptor GPR 119. Initially, GPR119 was consid- ered a potential new endocannabinoid receptor because of structural similarity and overlapping ligand selectively. Two of the major endogenous ligands discovered so far are the fatty acid amides oleylethanolamide (OEA, Fig. 4) and N-oleoyldopamine (Fig. 4), which were originally also classified as endocannabinoids. The process of de- orphanization of GPR119 and the demonstration that small molecule agonists are able to reduce body weight gain in rodents was first published in 2006 by Overton et al. (67) from OSI Pharmaceuticals (now Astellas). The receptor was shown to be Gαs-protein coupled and predominantly expressed in pancreatic islets and gastrointestinal tract in humans and rodents. GPR119 agonists were found to increase intracellular cAMP, which in turn leads to increased GLP-1 secretion from entero-endocrine cells (67–69). Very recently, it was shown that there is also cross-talk between the satiety hormone PYY and the GPR119 receptor (60). Together, these discoveries have generated considerable interest in the search for small- molecule GPR119 agonists as potential inducers of satia- tion, which is also illustrated by the robust activity in the patent area (70). Following the synthesis of the first ligands, including PSN632408 and AR-231,453 (Fig. 4), several pharmaceutical companies became active in developing GPR119 agonists and report activity from time to time. More examples and structures are available through the literature (70–72). Many of these compounds have shown interesting activities in animal models of type 2 diabetes and obesity, including a reduction of blood glucose without causing hypoglycaemia, a reduction of food intake and body weight, and reduced diabetes progression (69). The first compound that was advanced to the clinic, APD-668, was co-developed by Arena Pharmaceuticals (http://www.