Recent years have been very exciting for researchers working in the field of obesity. The discovery of the ob gene and its product leptin (109) has stimulated research in the field of genetics and molecular biology, with rapid advances being made in the understanding of weight-regulating mechanisms. This has led to the identification of a series of potential new targets for the treatment of obesity. However, experience has shown that it is not easy to translate this knowledge into clinically safe and effective pharmacological compounds. An important reason is that results found in laboratory animals are not always reproducible in human subjects. We will focus on a few of these newly identified targets and the corresponding compounds in development, which can be divided into those acting on energy intake and those acting on energy expenditure (110).
Appetite and food intake are modulated by several hormones and neurotransmitters acting in a complex interaction. Two major systems can be identified: the short-term regulation of food intake with cholecystokinin (CCK) and glucagon-like-peptide 1 (GLP-1) as major representatives and the long-term regulation of food intake through the leptin system. Recent data seem to suggest an interaction between these two weight-regulating systems (111-113).
Cholecystokinin and GLP-1 are both gastrointestinal hormones secreted by the duodenum in the presence of food. Cholecystokinin inhibits gastric emptying, contracts the pyloric sphincter and stimulates gallbladder contraction and pancreatic exocrine secretion (114). Intravenous infusion of cholecystokinin or GLP-1 has a satiety effect in both lean (115,116) and obese subjects (115,117). The satiety effect of cholecystokinin is mediated through its type A receptor found in the periphery and the central nervous system (118). Cholecys-tokinin agonists could be useful in the treatment of obesity but should be orally active, selective for the CCK-A receptor and should have a long biological half-life (119).
Glucagon-like peptide is an incretin hormone, stimulating the pancreatic secretion of insulin after food intake (120). In this context, GLP-1 has been extensively studied as an anti-diabetic agent and could be particularly useful for the obese type 2 diabetic patient through its action on both hyper-glycaemia and food intake (121). However, GLP-1 is metabolized very quickly by the dipeptidyl-pep-tidase IV (DPP-IV) enzyme (122), making it difficult to turn GLP-1 into a clinical useful therapeutic agent. Recently, considerable effort has been put into the development of DPP-IV resistant analogues of GLP-1 (123), DPP-IV inhibitors (124) and GLP-1 receptor agonists such as exendin-4 (125).
Since the discovery of leptin in 1994 (109), extensive research has shown that is more than just a simple mediator of energy intake and expenditure and that it plays a role in different physiological processes such as reproduction and insulin secretion (126).
Leptin was first discovered through the ob/ob mouse, where due to a mutation in the ob gene, no leptin is secreted (109). In these animals, treatment with leptin resulted in reduction of body weight (109). Obese humans, however, appear to have elevated leptin levels correlating with the amount of body fat (127). In a few cases mutations in the obese gene (128,129) or the leptin receptor gene (130) have been described. Treatment of a 9-year-old girl with a congenital leptin deficiency with recombinant lep-tin resulted in an important reduction of body weight, predominantly body fat (131).
The use of leptin as an anti-obesity agent is limited by the fact that it has to be given subcu-taneously and in very high doses, which could result in inflammatory reactions at the injection site. More promising perspectives will probably come from leptin analogues and leptin receptor agonists.
Leptin exerts its action through different neurot-ransmitters such as neuropeptide Y (NPY), glucagon-like peptide 1 (GLP-1), a-melanocyte-stimulating hormone (a-MSH), corticotrophin-re-leasing hormone (CRH) and cocaine and amphetamine regulated transcript (132,133). Extensive research has been done on the role of these peptides in the regulation of food intake in both animals and humans.
Two major pathways of post-receptor leptin signalling effects can be described: the NPY pathway leading to a decrease in food intake and the pro-opiomelanocortin pathway with an opposite effect.
NPY is one of the most potent stimulators of food intake (134) and six different receptor subtypes have been cloned. The type 1 and type 5 receptors appear to be most important receptors in the regulation of food intake (135,136). Several NPY receptor antagonists are now in different stages of pre-clinical and clinical development.
Melanocortins are peptides cleaved from its precursor pro-opiomelanocortin, with a-MSH being the most important melanocortin in the regulation of food intake (137). It binds to the melanocortin receptors MC3-R and MC4-R, resulting in a decrease in food intake (138). The agouti-related protein (AGRP) selectively antagonises MC3-R and MC4-R (139). Recently, melanin-concentrating hormone (MCH) was identified as another functional antagonist of a-MSH acting on a separate G-pro-tein-coupled receptor, somatostatin-like receptor 1 SLC-1 (140).
The most recently discovered families of hy-pothalamic peptides involved in the regulation of food intake are the cocaine and amphetamine regulated transcript peptides (CART) (141) and the orexins (142) or hypocretins (143), confirming the complex neuroendocrine system of weight regulation.
Drugs Altering Energy Expenditure The fir-Adrenergic Receptor
The adrenergic receptor, first discovered in the early 1980s (144), is mainly located in adipose tissue and plays an important role in adrenergic stimulation of lipolysis and thermogenesis in white and brown adipose tissue. Several pharmaceutical companies have developed ^r-agonists. Early compounds yielded positive results in animals but showed rather disappointing results in humans (145,146), which could in part be explained by the substantial differences between the animal and human receptor (144,147). After the cloning of the human receptor in 1989 (148), new highly selective compounds were developed (147). However, the effectiveness of ^-adrenergic receptor agonists remains questionable since the amount of brown adipose tissue in humans is very small (147).
Uncoupling proteins (UCPs) are mitochondrial proteins that uncouple adenosine triphosphate (ATP) production from mitochondrial respiration, producing heat leading to a net increase in energy utilization (149). UCP1 was identified in the 1980s and is mainly located in brown adipose tissue (150). Recently two new uncoupling proteins were identified: UCP2 is widely expressed in human tissues (151) and UCP3 (152) is found predominantly in skeletal muscle. Many papers have focused on the expression of UCP1 (153-155), UCP2 (156) and UCP3 (157) in obesity and type 2 diabetes, yielding conflicting results.
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