Current Medicinal Chemistry - Central Nervous System Agents - Volume 3, Issue 2, 2003

The proglucagon-derived peptides glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are released from gut endocrine cells in response to nutrient ingestion, and regulate gastric acid secretion, gastrointestinal motility, nutrient absorption, glucose homeostasis and cell proliferation and survival. GLP-1 and GLP-2 are also synthesized in the central nervous system, predominantly in neurons of the nucleus of the solitary tract in the brainstem, and to a lesser extent in the hypothalamus. Intracerebroventricular (ICV) administration of GLP-1 inhibits food intake in rodents and ICV GLP-1 activates neuroendocrine circuits, the sympathetic nervous system, and pathways coupled to transduction of an interoceptive stress response. Interruption of GLP-1R signaling in the rodent brain attenuates the development of a conditioned taste response and fos-activation following exposure to noxious agents such as lithium chloride. Although peripheral administration of GLP-1 to human subjects is associated with inhibition of gastric emptying, feelings of satiety, and reduction of food intake, chronic treatment of diabetic subjects with GLP-1R agonists prevents weight gain, but is not associated with major weight loss over 8-12 week treatment periods. Although ICV injection of GLP-2 also inhibits food intake, GLP-2 is much less anorexic compared to GLP-1. Both GLP-1 and GLP-2 exert direct cytoprotective and regenerative actions, suggesting that activation of glucagon-like peptide receptor signaling may attenuate cellular injury in the CNS. As peripheral administration of GLP-1R agonists activate CNS GLP-1R systems, the biology of glucagon-like peptides in the brain is directly relevant to pharmaceutical use of glucagon-like peptide agonists for the treatment of human disease.

During the past decades, obesity has become a major health problem worldwide. Balance of energy homeostasis is one of the most vital functions exerted by animals, and a very complex network of central and peripheral signaling systems is involved in its regulation. Recently, the cannabinoid receptor type 1 (CB1) and the endogenous cannabinoid system emerged as very important components for the control of energy balance. This system is proposed to regulate feeding behavior both at central and peripheral levels. In particular, the endogenous cannabinoid system is under the control of peripheral signaling systems such as leptin in the hypothalamus and might, in turn, regulate the action of hypothalamic feeding-regulatory neuropeptides. Endocannabinoids have also been proposed to participate in the rewarding properties of food in mesolimbic circuits of the brain. Moreover, the endogenous cannabinoid system regulates food intake in the gastrointestinal tract, possibly by modulating peripheral neuronal and hormonal responses to changes in feeding status. The main goal of this review is to highlight the most recent advances and concepts regarding the role of the endogenous cannabinoid system in control of energy balance and to discuss the prospectives for the use of CB1 antagonists in the therapy of obesity.

Human obesity represents a major threat to global well-being, and a better understanding of its pathogenic mechanisms may lead to the development of effective therapeutic strategies. In this article, we will review the existing literature dealing with the role of serotonin in the pathogenesis of obesity. Using a number of models, we demonstrate that abnormal hypothalamic serotonergic neurotransmission and / or deranged receptor expression / sensitivity exists, and that these are closely associated with changes in the concentrations of dopamine, another hypothalamic monoamine closely involved in the regulation of food intake. However, it is still difficult to ascertain whether these abnormalities are acquired in response to chronic overingestion resulting in obesity, which then drives further increases in food intake to preserve the status quo, or whether these are due to primary factors. The pivotal role of central serotonin in obesity is also strengthened by the evidence that the drugs licensed to interfere with food intake in obese patients involve the serotonergic system. But since their use, including sibutramine, may lead to potentially severe side effects, alternative strategy to increase hypothalamic serotonergic activity is also proposed.

In this article, we describe recent advances in the study of novel orphan GPCR ligands related to obesity, focusing on melanin-concentrating hormone (MCH), neuropeptide W (NPW), neuropeptide B (NPB) and galanin-like peptide (GALP).An endogenous ligand of orphan G-protein-coupled receptor (GPCR), SLC-1 (MCH-R1), was isolated from rat brain and revealed to be MCH. Phenotypic analyses of genetically engineered animals indicated that the MCH-SLC-1 / MCH-R1 axis is relevant to feeding behavior and energy homeostasis. We developed MCH receptor antagonists and found that they could inhibit food intake stimulated by central administration of MCH.NPW was isolated from porcine hypothalamus as a ligand for orphan GPR8 and found to bind to both GPR7 and GPR8 at similar effective doses. Results of intracerebroventricular administration of NPW to rats suggested that it regulated feeding behavior and the neuroendocrine system, although further study is required to confirm the physiological functions of NPW.In addition, we isolated NPB, which was closely related to NPW in structure, from bovine hypothalamus as a GPR7 ligand and found that it was modified with bromine at position C-6 of the indole ring of the N-terminal Trp residue. From the distribution of the NPB mRNA in the rat brain, NPB was suggested to be involved in the regulation of feeding and the neuroendocrine system as well as memory and learning.GALP was isolated from porcine small intestines as a ligand for galanin subtype receptor GALR2. The most interesting feature was that GALP-neurons were specifically localized to the arcuate nucleus in rats and under the positive regulation of leptin, suggesting that GALP mediates the anorexic activity of leptin.

Recent advance in adipocyte biology revealed that adipose tissue is a secretory organ. Such fat-derived secretory factors are now called adipocytokines, conceptually. Adipocytokines known to date include leptin, TNF-α, resistin, PAI-1, and adiponectin. Physiological production and secretion of adipocytokines maintains metabolic and vascular homeostasis, by functioning to adipocyte itself through auto- and para-crine fashions, and remote organ through blood stream. Dysregulated production of adipocytokines, too much or too little, in obesity and lipodystrophy, lead to the development of metabolic syndrome including insulin resistant diabetes and vascular disease. Restoring the plasma levels of adipocytkines have been shown to reverse such metabolic syndrome associated with obesity and lipodystrophy. Adipocytokines are now becoming a central target to tackle the metabolic syndrome.

Although organisms normally regulate energy intake and expenditure in a precise manner, certain disease states, such as cancer, may disrupt this regulatory balance resulting in anorexia (reduced energy intake) in the presence of elevated metabolic rate. The search for mediators of this dysfunction has focused upon neuropeptides localized primarily in the hypothalamus and known to be potent regulators of feeding in normal circumstances. Of the compounds known to stimulate feeding in normal animals, dysfunction of neuropeptide Y (NPY) has been the focus of much research in experimental cancer anorexia studies. These experiments have shown NPY-induced feeding to be refractory in tumorbearing (TB) rats, with continuous infusion or repeated injections not reversing the anorexia. The release of NPY in the hypothalamus is also decreased in TB rats shortly after the development of anorexia. Although whole hypothalamic concentration of NPY is decreased prior to the onset of anorexia, concentrations are elevated in the cell body containing arcuate (ARC) nucleus, but are decreased in the paraventricular (PVN) nerve terminal area as compared to pair-fed (PF) controls. NPY gene expression is also increased in the ARC-containing ventromedial hypothalamus of TB and PF rats, but NPY mRNA was not increased in the PVN-containing dorsomedial area. Many of the changes in NPY level and gene expression may be secondary to decreased leptin and insulin in anorectic TB rats. NPY receptor binding is also altered in TB rats, with decreased affinity occurring prior to the onset of anorexia. Several anorexia-producing neuropeptides appear to interact with NPY in TB rats, which may down-regulate its normal control of feeding. Corticotropin releasing factor (CRF) is elevated in the hypothalamus of TB rats, and CRF has been shown to inhibit NPY-induced feeding. Another anorectic peptide of the melanocortin family, alpha-melanocyte stimulating hormone (α-MSH), decreases NPY-induced feeding and release. Since it appears that both CRF and a-MSH may be tonically-active, NPY may normally induce feeding through inhibiting these systems. In anorexia, the level of this tonic inhibition may be greater than can be overcome by NPY. Cytokines also appear to be involved in NPY dysfunction in cancer anorexia, with hypothalamic interleukin-1B (IL-1B) message being elevated in anorectic TB rats. In addition, IL-1B and NPY have mutual inhibitory effects on feeding. However, IL-1B did not affect NPY release from hypothalamus. Other possible circulating mediators of the anorexia in TB rats may be elevated ammonia, lactate and lipids as well as dysfunctional intracellular signal transduction. Therefore, it appears that NPY function is being inhibited by alterations in other neurochemicals, and simply administering NPY analogs may not reverse cancer anorexia.