Current Medicinal Chemistry -Central Nervous System Agents, Volume 3, No. 3, 2003
Contents
Medicinal
Strategies in the Treatment of Obesity
Guest
Editor: Akio Inui
Neuroendocrine Targets for the Treatment of Obesity:
Physiological Roles and Unrealized Opportunities Pp.141-155
J.A. Harrold , G. Williams and S. Wong
Fat Digestion and its Role in Appetite
Regulation and Energy Balance –The Importance of Enterostatin
and Tetrahydrolipstatin Pp.157-175
Andreas Lindqvist
and Charlotte Erlanson-Albertsson
Ghrelin: A Gastric Peptide that Regulates
Hypothalamic Control of Feeding
Pp.177-188
H. Yamaguchi , M. Nakazato
, and K. Kangawa
Keeping Obesity and Metabolic Syndrome at Bay
with Central Leptin and Cytokine Gene Therapy Pp.189-199
S.P. Kalra and P.S. Kalra
The CNS Melanocortin
System: A Biological Weapon Against the Threat of Obesity Pp.201-215
M.M. Hagan , P.C. Chandler and P.K. Wauford
Melanin-Concentrating Hormone as a Metabolic
and Cognitive Regulatory Factor
Pp.217-227
Goro Katsuura , and Akio Inui
Roles of Orexin in
Regulation of Energy Homeostasis Pp.229-241
Takeshi Sakurai
The CRF Peptide Family in Appetite Regulation
and Energy Balance
Pp.243-255
Hisayuki Ohata and Tamotsu Shibasaki
b3-Adrenergic Receptors: Really Relevant Targets
for Anti-Obesity Drugs?
Pp.257-273
E. Nisoli , C. Tonello and M.O. Carruba
Abstracts
[Back to top] Neuroendocrine Targets for the Treatment of Obesity:
Physiological Roles and Unrealized Opportunities
J.A. Harrold , G.
Williams and S. Wong
In recent years, knowledge has advanced rapidly about the signals which indicate the body’s energy requirements and the neuronal circuits that can sense and respond appropriately to these signals, by effecting changes in food intake and energy expenditure.
Much interest has focused on the circulating hormones leptin and insulin. Leptin is expressed predominantly in white adipose tissue and its circulating levels are broadly proportional to fat mass (the body’s major energy store). Insulin also circulates at levels that reflect adiposity. Both hormones can signal fat mass to the brain: they readily enter the hypothalamus and other brain regions, where they target specific neuronal populations with the overall effect of inhibiting feeding and increasing energy expenditure. Key hypothalamic targets for both leptin and insulin include neurons expressing the orexigenic (appetite-stimulating) peptide neuropeptide Y (NPY), which are inhibited by both hormones.
The gut also generates nutritional signals that reach the brain. These include cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and the recently identified PYY(3-36), all peptides released from the gut after feeding and which act both centrally (and peripherally in the case of CCK and GLP-1) to inhibit hunger. By contrast, ghrelin is expressed mainly in the stomach and its circulating concentrations rise during fasting; - it acts to stimulate food intake, in part via stimulation of the hypothalamic NPY neurons.
These and other signals, describing different aspects of energy balance, converge upon and are integrated by specific neuronal populations in the hypothalamus. Mutations in key components of these circuits underlie some syndromes of genetic obesity in rodents, but are responsible for only a small minority of human obesity – which is mostly due to adverse lifestyle. Various abnormalities of leptin, insulin and hypothalamic peptides have been identified in dietaryinduced obesity in rodents, which is more closely analagous to ‘common’ human obesity. The relevance of many of these various players to human energy homeostasis remains uncertain, but some promising novel anti-obesity drugs; are likely to emerge in the next few years.
[Back to top] Fat Digestion and its Role in Appetite
Regulation and Energy Balance –The Importance of Enterostatin
and Tetrahydrolipstatin
Andreas Lindqvist
and Charlotte Erlanson-Albertsson
A high fat intake, together with an inability to match lipid utilization of a high-fat intake, is correlated with obesity in man. In this review enterostatin, a peptide, which specifically reduces fat intake, is described. Enterostatin is formed in the intestine by the cleavage of pancreatic procolipase, the remaining colipase serving as an obligatory cofactor for pancreatic lipase during fat digestion. Enterostatin is also produced in chief cells of the stomach as part of procolipase as well as in enterochromaffine cells independent of procolipase, most frequent in the antral part of the stomach extending all along the intestine down to the ileum. Enterostatin has been found to increase during fat feeding, where it is found in the intestinal lumen, in the lymph as well as in the circulating blood. When reducing food intake, enterostatin behaves as a physiological satiety substance, inducing early satiety. A raised production of serotonin has been measured centrally. During long-term treatment, enterostatin has been found to reduce body weight in the rat and mouse. A reduced body weight may be explained by a decreased food intake and an increased energy expenditure through activation of the sympathetic nervous system and increased expression of uncoupling protein 1 in brown adipose tissue. Enterostatin also increases the expression of uncoupling protein 2 in the gastrointestinal tract. The mechanism of action of enterostatin suggests the involvement of the opioid system being inhibited by enterostatin. Another target protein for enterostatin is the beta-subunit of F1F0-ATPase. These two target proteins may explain the appetite regulating effects of enterostatin as well as the thermogenic effects.
[Back to top] Ghrelin: A Gastric Peptide that Regulates
Hypothalamic Control of Feeding
H. Yamaguchi , M. Nakazato , and K. Kangawa
Ghrelin, a novel growth-hormone-releasing peptide isolated from human and rat stomach, is a 28-amino acid peptide with a posttranslational acylation modification that is indispensable for its activity. Ghrelin stimulates secretion of growth hormone, food intake, and body weight gain. This review will focus on the discovery, structural characteristics, tissue distribution, and physiological functions of ghrelin, as well as the regulation of its expression and secretion. Future directions of clinical application of ghrelin as an anabolic peptide are discussed.
[Back to top] Keeping Obesity and Metabolic Syndrome at
Bay with Central Leptin and Cytokine Gene Therapy
S.P. Kalra and P.S. Kalra
The incidence of obesity and metabolic syndrome along with the annual cost of treating obesity and related metabolic disorders are rising steeply world wide. In this article, the potential of gene therapy application directly into the hypothalamus, a CNS site involved in integration of energy homeostasis, as a therapeutic modality is reviewed. We engineered a non-immunogenic, non-pathogenic recombinant adeno-associated virus vector to encode leptin, leptin receptor, or the cytokines, leukemia inhibitory factor and ciliary neurotrophic factor. A single injection of virus vectors encoding any of these genes either intraventricularly or into selected hypothalamic sites of wild type or genetically obese rodents curtailed the gradual age-related and rapid high fat diet-induced obesity for long periods. Parameters of metabolic syndrome, hyperleptinemia, hyperinsulinemia and hyperlipidemia were normalized along with fat depletion and increased non-shivering thermogenic energy expenditure either alone or in association with voluntary reduction in food intake. Operation of hypothalamic appetite and energy regulating network was correspondingly modified to conform with the anorectic and obesity suppressing effects of central leptin and cytokine gene therapy. These results advocate central gene therapy as a viable alternative to curb the rising tide of obesity and associated metabolic diseases with or without a voluntary reduction in food intake.
[Back to
top]
The CNS Melanocortin System: A Biological Weapon
Against the Threat of Obesity
M.M. Hagan , P.C. Chandler and P.K. Wauford
Commensurate with the last decade’s increasing prevalence of obesity is the number of breakthroughs in the physiology of energy regulation. Primary of these is the role played by the CNS melanocortin 3 and 4 receptors (MC3/4R). The MC3/4 ligand, alpha-melanocyte stimulating hormone, is a primary anti-obesity target due to its anorectic and catabolic actions. A level of complexity is introduced by agouti related peptide, an endogenous antagonist at the MC3/4R that exerts orexigenic and anabolic functions. Here we evidence the utility of the MC system to treat obesity by reviewing the long-lasting changes in food intake, selection of fat, propensity to develop or resist obesity, and ability to burn energy that occurs in knockout mice, and in animals administered endogenous and synthetic MC ligands. Further evidence is conferred by the high frequency of MC4R mutations among human monogenetic obesities. As a downstream regulator of leptin and insulin, and integrator of opioid and dopamine functions, the MC system is positioned to override leptin and insulin resistance, as well as addictive-like regard of food that contributes to obesity. We review advances in identification of vital structural elements in MC binding, autoregulation and inverse agonist theories, the development of novel potent and selective non-peptide ligands, and non-traditional biochemical approaches to achieve pseudoagonist effects. Finally we review the status of small molecule ligands, outcomes of the clinical studies testing MC compounds, and suggest requirements of the optimal anti-obesity drug, novel delivery strategies, and the adjunct use of fatty acid oxidation elements to treat obesity.
[Back to top] Melanin-Concentrating Hormone as a Metabolic and Cognitive Regulatory
Factor
Goro Katsuura , and Akio Inui
Melanin-concentrating hormone (MCH) is an orexigenic cyclic 19 amino acid neuropeptide, and the cell bodies of MCH-containing neurons are mainly present in the lateral hypothalamus and zona incerta that are recognized as the feeding center of mammalian brain. MCH receptors, MCH-1R and MCH-2R are also widely distributed in the brain areas, especially in the hippocampus, amygdala and cerebral cortex. These findings suggest that MCH may modulate the energy homeostasis and other activities of central nervous system. Central administration of MCH increases food intake and decreases energy expenditure. Diet-induced and genetically obese animals have increase in MCH tone in the brain which is suppressed by leptin treatment. Moreover, MCH-transgenic mice exhibit obese syndromes when fed on high-fat diet. On the other hand, the MCH- or MCH-1R-deficient mice showed the resistance to obesity induced high-fat diet. Furthermore, MCH produces anxiety and increases the hippocampal synaptic efficacy, resulting in the enhancement of learning and memory processes. Non-peptide antagonists for MCH-1R prevented the high-fat diet-induced obesity, and possess anxiety and antidepressant effect. These finding indicate the involvement of MCH in the development of obesity, memory and emotion. MCH receptor antagonist might be useful for the treatment of obese syndrom including psychological disorder related obesity.
[Back to top] Roles of Orexin in Regulation of Energy
Homeostasis
Takeshi Sakurai
The efferent and afferent systems of orexin neurons suggest interactions between these cells and important feeding centers in the hypothalamus, arousal and sleep-wakefulness centers in the brainstem, sympathetic and parasympathetic nuclei, and the limbic system. Numerous studies have documented that acute intracerebroventricular administration of orexin dose-dependently increases arousal-associated behavioral and physiological processes including food intake, waking time, motor activity, and metabolic rate, as well as heart rate and blood pressure in many species. Furthermore, it is likely that orexin-mediated food intake results partly from stimulation of feeding pathways in the hypothalamus such as those involving the NPY pathway. Recent electrophysiological studies have shown that orexin neurons are regulated by metabolic cues, including leptin, glucose, and ghrelin. Thus, orexin neurons have the requisite anatomical connections and interactions with hypothalamic feeding pathways, and regulation by circadian and nutritional factors to suggest that they may be an important cellular and molecular link in the integration of sleep and energy homeostasis.
[Back to top] The CRF Peptide Family in Appetite Regulation and Energy Balance
Hisayuki Ohata and Tamotsu Shibasaki
The physiological roles and pharmacological profile of the corticotropin-releasing factor (CRF) peptide family and their receptors are described. Urocortin, urocortin II, and stresscopin/urcortin III are members of this family in rodents and humans. In the central nervous system, these peptides exert actions through their main receptor subtypes CRF1 and CRF2. The current review discusses the results of many studies on the role(s) of the CRF peptide family and of CRF receptors in the regulation of food intake and energy expenditure.
[Back to top]
b3-Adrenergic
Receptors: Really Relevant Targets for Anti-Obesity Drugs?
E. Nisoli , C. Tonello and M.O. Carruba
In simple terms, obesity is a chronic disorder of energy imbalance, for which a long-term excess of energy intake over expenditure leads to the storage of that excess energy as white adipose tissue. In this article, we review b3- adrenergic receptor agonists, agents in development both to increase energy expenditure and counteract energy expenditure decline following a calorie restriction program. b3- adrenergic receptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. b3-adrenergic receptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, b3-adrenergic receptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify b3-adrenergic receptor agonist drugs because the pharmacology of both b3- and b1- adrenergic receptors can vary. Since their discovery in 1983, hundreds different compounds have been synthesized with b3-adrenergic receptor agonist profile. We identified in the literature 32 molecules in development: 9 molecules are in discovery phase (from 10 October 2001 to 25 November 2002: five molecules in 2002 and 4 in 2001), 5 molecules are in different clinical phases, 10 molecules were discontinued, for 8 molecules no development was reported. Here we have tried to demonstrate that the preclinical and clinical studies on b3-adrenergic receptors and b3-adrenergic receptor agonists as anti-obesity drugs is yet active, even if no conclusive therapeutic agents have been identified. With the huge recent increase in our knowledge on the molecular processes involved in adipose cell biology and adaptive thermogenesis, there may yet be a future for b3-adrenergic receptor agonists.