Current and Future Drug Targets in Weight Management Inhibitors of Low-Affinity Sodium-Dependent Glucose Co-transporters (SGLT2) Compared to the previous categories discussed, this target represents a different potential approach for weight loss. The sodium-glucose co-transporter-2 (SGLT2) is a low- affinity transport system that is specifically expressed in the kidney and plays an important role in renal glucose re- absorption in the proximal tubule. Competitive inhibition of SGLT2, leading to enhanced glucose and energy loss through the urine, was initially regarded a promising new therapeutic strategy for the treatment of hyperglycaemia in patients with type 1 or type 2 diabetes (see (46) for a recent review). However, some compounds are now also under- going investigation for their potential effect on body weight. These include serglifozin (GSK-869682; clintrials.gov NCT00297180), canaglifozin (JNJ-28431754; clintrials.gov NCT00650806) and remogliflozin etabonate (GSK- 189075; clintrials.gov NCT00494767). Johnson and John- son plan to file their canaglifozine before 2013 (47). Intestinal Microbiota as Future Target for Weight Management? A potential future strategy for weight loss that is currently receiving increasing attention is selective modulation of the intestinal micro flora. Some years ago, Gordon and co- workers (48,49) discovered that intestinal bacteria appear to have an important effect on body weight. In addition, certain antibiotics can increase body weight in rats and mice, and human data indicate that the combination of vancomycin plus gentamycin is accompanied by a signifi- cant weight gain (50). Several mechanisms have been suggested, including the phenomenon of “energy harvest- ing” by the micro flora, production of specific short-chain fatty acids interacting with certain receptors including GPR41 and GPR43 (51), and changes in the pro-/anti- inflammatory balance in the gut. TARGETS FOR REDUCING APPETITE OR INDUCING SATIETY OR SATIATION Pharmacological modulation of human eating behavior has proven to be extremely complex. People do not only eat to satisfy their hunger or appetite, but also for many other reasons, including sensory stimulation, sensory hedonics, in response to stress, for social interaction, against boredom, etc. (29–31,52,53). Several pathways are involved in regulating eating behavior with many redundant and compensation mechanisms in place. Before and during eating, sensory effects are generated through the taste, smell, temperature and texture of food. Cognitive effects 1797 play a role in the beliefs about the properties of the foods being eaten and their effects. Post-ingestive factors include the effects of gastric distension, rate of gastric emptying, release of intestinal hormones into the circulation and neural signaling via the Nervus vagus (see (54) for review). Signals and hormones originating from the GI tract are commonly called satiety signals and satiety hormones, respectively. They include the pancreatic hormone gluca- gon, cholecystokinin (CCK), GLP-1, PYY, etc. It should be noted that the term satiety hormones may be somewhat confusing, since most of them promote a process called satiation, which serves as trigger of meal termination. Meal termination is also stimulated by circulating levels of glucose, amino acids and lipids, which are directly sensed by the brain or through peripheral receptors (55). By contrast, the term satiety is typically used to describe processes that inhibit further eating during postprandial periods, determining meal frequency. Blood glucose con- centration activates gluco-receptors in the hypothalamus, either acting to up-regulate hunger when blood glucose levels fall or up-regulate satiety when glucose concentra- tions rise. In the longer term, deposition of fat may lead to control of appetite by neuronal and hormonal signals via leptin. Within the central nervous system, systems involved in eating behavior share many mediators and pathways involved in, for example, the regulation of metabolism and mood state. This partly explains why several compounds with a relatively broad spectrum of activities have shown unacceptable side effects in the past. Vice versa, there are also several CNS drugs developed for other indications that show effects on eating behavior. For the purpose of this review, two main approaches will be distinguished here: – – Modulation of nutrient sensing within the GI tract or through interference with signals transmitted to the brain or peripheral organs. Modulation of signal processing within the CNS, for example by interfering with neurotransmitter concen- trations or activity. NUTRIENT SENSING WITHIN THE GI TRACT AND SIGNALLING TO THE BRAIN Generation of Satiety Signals in the GI Tract According to most of the present views, endocrine biochemical signals are not regarded as major drivers for meal onset. So far, the only exception seems to be ghrelin, which is an orexigenic (stimulating eating) peptide hor- mone, surging just before meals and suppressed by ingested nutrients (54,56). By contrast, satiation is a process that is