Current Drug Targets, Volume 6, No. 2, 2005
Contents
Appetite
Regulation: Future Directions in Obesity Treatment
Guest
Editor: Jason C.G. Halford
Editorial
Jason
C.G. Halford
Section 1: Peripheral Episodic Satiety Factors
The Role of Apolipoprotein AIV on the Control
of Food Intake Pp.145-151
Xiaofa
Qin and Patrick Tso
Ghrelin and Energy Balance: Focus on Current
Controversies Pp.153-169
David
E. Cummings, Karen E. Foster-Schubert and Joost Overduin
Peptide YY: A Potential Therapy for Obesity Pp.171-179
D.
Renshaw and R. L. Batterham
Pancreatic Amylin as a Centrally Acting
Satiating Hormone Pp.181-189
Thomas
A. Lutz
Section 2: Central Targets within the Appetite and
Energy Regulation Systems
Modulation of Eating by Central Catecholamine
Systems Pp.191-199
Paul
J. Wellman
Serotonin (5-HT) Drugs: Effects on Appetite
Expression and Use for the Treatment of Obesity Pp.201-213
Jason
C.G. Halford, Joanne A. Harrold, Clare L. Lawton and John E. Blundell
Cannabinoids and the Regulation of Ingestive
Behaviour Pp.215-223
S.P.
Vickers, and G.A. Kennett
The Hypothalamus and Obesity Pp.225-240
Peter
J. King
Abstracts
[Back to top] Editorial
Jason C.G. Halford
This special edition focuses on peripheral and central mechanisms critical to the expression of appetite that either can or could be exploited to treat obesity via the reduction of energy intake. Obesity is a key risk factor for a variety of non-communicable diseases and after smoking is the single biggest lifestyle factor associated with morbidity and mortality. The increasing prevalence of global obesity and our understanding of its central role in what is now being call the metabolic syndrome has lead to an increasing demand for new drugs to manage patients’ weight. With this new understanding, the development of effective anti-obesity drugs is now of critical interest those trying to treat diabetes and cardiovascular problems, and those trying to prevent the same conditions in over weight patients.
Reducing energy intake it not the only way of inducing weight loss, and targeting appetite is not the only meaning of reducing energy intake. Despite this, targeting appetite regulatory mechanisms to reduce food intake has historically been the most popular pharmacological approach to treating obesity. It has yielded drugs such as fenfluramine, d-fenfluramine and more recently sibutramine. These drugs have all been effective at reducing and controlling patients’ body weight, a clinical effect directly related to their hypophagic action. Their drawback has been their side effect profiles (primary pulmonary hypertension in the case of fenfluramine and increases in blood pressure and heart rate in the case of sibutramine). However, all these drugs reduced food intake by reducing pre-meal hunger and strengthening within meal satiation to reduce meal size. They also appear to strength the between meal state of satiety, preventing compensatory increases in meal number and reducing between meal snacking, an important trigger of caloric over-consumption.
The reduction of between meal intake is particular important. Snacks tend to contain higher levels of sugar and/or fat. This makes them energy dense and due to their relatively small size, snacks appear to have a weaker impact on short-term appetite regulatory mechanisms promoting increases in daily caloric consumption that the body finds particularly difficult to correct for. Drugs like d-fenfluramine have been shown to decrease in intake of dietary fat by selectively suppressing snack intake. It is not clear whether the drug makes the consumption of high fat energy dense snack foods less appealing or the reduction in snack intake can be attributed purely to strengthening of post meal satiety. However, any drug that selectively reduces the consumption of obesity promoting of food items such as snacks would be of particular therapeutic value.
This special edition is divided into two sections. Section one is devoted to peripheral episodic satiety factors. These are the factors, which with the exception of Ghrelin, are generated in the gut or in other peripheral sites by the consumption of food. Exogenous infusions of these factors into the brain and/or the peripheral also produce strong hypophagic responses in rodents. From the research detailed within these reviews it would seem that all these factors (Apoliproprotein A-IV, PYY3-36 and Amylin) enhance central anorexigenic systems and/or inhibitor orexigenic systems located in or projecting into the hypothalamus. Ghrelin, on the other hand, is a gut factor that appears to stimulate food intake, possible by activating the same hypothalamic orexigenic systems. Of course not all peripheral satiety factors are included in this special edition. There are no reviews of Cholecystokinin (CCK), Gastrin Releasing Peptides (GRP), Glucagon-Like Peptide 1 (GLP-1) and Enterostatin. However, we have reviewed these targets elsewhere and refer interested readers to those review articles (1, 2). Instead reviews of novel and perhaps controversial targets have been included many of which are now the focus of drug development, with some potential treatments quickly passing into early clinical trials. For instance a Peptide YY (PYY), based treatment called AC162352 from Amylin, started phase 1 clinical trials in 2004. Similarly, a PYY3-36 nasal spray from Nastech Pharmaceuticals and Merck has completed phase 1 development.
Section two is devoted to central targets within the appetite and energy regulations systems. Existing appetite suppressing drugs, such as the fenfluramines and sibutramine have induced reductions in food intake by acting on central appetite regulatory targets, namely serotonin (5-HT) and nor-adrenaline (NA). In this section two reviews will consider both the 5-HT and NA systems. Such reviews are timely considering the recent decision of GlaxoSmithKline to develop their novel Nor-adrenergic and Dopaminergic reuptake inhibitor (an active metabolite of bupropion hydrochloride called Radafaxine), and the continued development of selective 5-HT2C receptor agonists by various companies, to treat obesity. Indeed, the selective 5-HT2C receptor agonist APD356 from Arena Pharmaceuticals is currently starting phase 2 in clinical trials.
However, perhaps the timeliest review is that of the endocannabinoid system. The endocannabinoid CB1 receptor antagonist Rimonabant (Acomplia) has nearly completed phase 3 development. The RIO (Rimonabant in obesity) program of four clinical trials (RIO North American, RIO Europe, RIO lipids and RIO Diabetes) is near completion and the effects of the drug on body weight and risk factors for obesity related disease have been established. The effects of two doses of the drug (5 mg and 20 mg) have been assessed in near 6000 patients over one or two years of treatment. It appears the drug produces greater placebo subtracted weight loss than existing anti-obesity treatments (3). This year the drug developer, Sanofi Aventis will seek approval for the drugs use for the treatment of obesity. This special edition concludes with a review of the orexigenic and anorexigenic neuropeptides systems of the hypothalamus with a view to predicting the mechanisms of action of drugs which could potentially pass into clinical development in the next 5 years. Numerous drug companies have focused on these systems in the hope of developing candidates for anti-obesity programs and it is likely we may see the first of these enter phase 1 trials in the next 12 months.
I sincerely hope the reader enjoys this special edition. In its conception and development I have tried to provide the broadest view of the various target systems involved in appetite regulation and how future exploitation of them may be used to treat obesity. It only remains for me to thank the authors of the various reviews for their hard work and commitment and Miss Lisa D.M. Richards for her help with the preparation of the manuscript.
1. Halford, J.C.G.; Cooper, G.D.; Dovey, T.M.; Ishii, Y.; Rodgers, R.J.; Blundell, J.C.G. (2003) Curr. Med. Chem. - Central Nervous System Agents, 3, 283-310.
2. Halford, J.C.G.; Dovey, T.M.; Cooper, G.D.; (2004) Curr. Drug Targets, 5, 221-240.
3. Halford, J.C.G. (2004) Curr. Drug Targets, 5, 637-46.
Disclosure: Dr. Halford received research support from Sanofi Aventis and GlaxoSmithKline in 2004.
[Back to top] The Role of Apolipoprotein AIV on the Control
of Food Intake
Xiaofa
Qin and Patrick Tso
Apolipoprotein AIV (apo AIV) is a protein synthesized by the human intestine. The synthesis and secretion of apo AIV are stimulated by fat absorption. In 1992, Fujimoto et al. [1] first demonstrated that apo AIV is a satiety signal secreted by the small intestine following the ingestion of a lipid meal. This initial observation was followed by a number of studies supporting apo AIV’s role as a satiety signal. This review article discusses the regulation of synthesis of apo AIV in the small intestine as well as the hypothalamus. In addition, the evidence that apo AIV is a satiety factor and its role of apo AIV in diet induced obesity will be discussed. We hope this review will serve as a catalyst to promote apo AIV research in the future. With most of the required reagents available, e.g., the apo AIV knockout and transgenic animals and apo AIV antibodies, the next few years should bring considerable new information on the function of apo AIV.
[Back to top] Ghrelin and Energy Balance: Focus on Current
Controversies
David
E. Cummings, Karen E. Foster-Schubert and Joost Overduin
Ghrelin is an enteric peptide that is the only known circulating appetite stimulant. This feature of the hormone has garnered widespread attention, as reflected by more than 1000 scientific papers featuring ghrelin that have been published since the first reports of its orexigenic actions, approximately four years ago. In this review, we discuss data that support roles for ghrelin in the short-term regulation of pre-meal hunger and meal initiation, functioning as a unique orexigenic counterpart to short-acting gastrointestinal satiation factors, such as cholecystokinin (CCK). We also highlight evidence indicating that ghrelin satisfies recognized criteria to be viewed as a participant in long-term body-weight regulation – a potential anabolic counterpart to the traditional adiposity hormones, leptin and insulin. We then discuss the following controversial questions in ghrelin research and offer our opinions regarding these debates. (1) Is ghrelin synthesized within the brain? (2) How does ghrelin increase food intake? (3) Does des-acyl ghrelin have a physiologic function? (4) Are there receptors for ghrelin other than GHS-R1a? (5) Does ghrelin regulate insulin secretion? (6) Does ghrelin regulate gastrointestinal motility? (7) Can ghrelin or ghrelin-receptor agonists be used to treat wasting conditions? Finally, we offer a speculative model of ghrelin as a thrifty gene product that evolved to help animals consume and store fat well, thereby increasing their chances of survival during times of famine. We suggest that ghrelin is a "saginary" hormone, from the Latin, saginare, which means, "to fatten".
[Back to top] Peptide YY: A Potential Therapy for Obesity
D.
Renshaw and R. L. Batterham
Obesity now represents a modern epidemic in western society with major health and economic consequences. Unfortunately, previous pharmacological approaches to the treatment of obesity have been associated with life-threatening side effects and limited efficacy. Over recent years there has been a marked increase in our understanding of the physiological mechanisms that regulate body weight and how these are perturbed in obesity. One therapeutic strategy is to develop drugs which both mimic and enhance the body’s own satiety signals. The gut hormone peptide tyrosine tyrosine (PYY), which is released postprandially from the gastrointestinal tract, has recently been shown to be a physiological regulator of food intake. Peripheral administration of PYY reduces feeding in rodents via a mechanism which requires the Y2 receptor and is thought to primarily involve modulation of the hypothalamic arcuate nucleus (ARC) circuitry. In humans a single 90-minute infusion of PYY has been shown to markedly reduce subsequent 24-hour caloric intake in lean, normal-weight and obese subjects. Moreover, obese subjects have been found to have low levels of fasting and postprandial PYY suggesting a role for this hormone in the pathogenesis of obesity. Although studies examining the effects of chronic peripheral administration of PYY to humans are awaited, the results from continuous infusion studies in a number of obese rodent models are encouraging with reductions in food intake, body weight and adiposity observed. Potential therapeutic manipulations based on the PYY system include development of Y2 agonists, exogenously administration of PYY or increased endogenous release from the gastrointestinal tract.
[Back to top] Pancreatic Amylin as a Centrally Acting Satiating Hormone
Thomas
A. Lutz
This review summarizes the present knowledge concerning the anorectic action of the pancreatic hormone amylin. It focuses mainly on the role of amylin as a short term satiating peptide. Since there is some evidence however that basal amylin levels might play a role in the long term control of food intake and/or body weight, this aspect will be discussed briefly towards the end of this review.
Concerning amylin as a satiating hormone, it is well established that amylin is released during meals, and that exogenous amylin leads to a dose-related reduction in meal size. Amylin has a rapid onset and brief duration of action. The area postrema (AP) plays a predominant role in peripheral amylin's satiating effect, involving a direct activation of AP neurons by blood-borne amylin. The nucleus of the solitary tract (NTS) relays this effect to higher brain structures, the lateral parabrachial nucleus, and possibly the central nucleus of the amygdala and the bed nucleus of the stria terminalis. Amylin’s anorectic effect may in part be due to reduced expression of orexigenic neuropeptides in the lateral hypothalamic area.
The anorectic action of amylin is one important factor in amylin's overall role to control the influx of nutrients into the circulation. By reducing food intake, gastric acid secretion, limiting the rate of gastric emptying and diminishing pancreatic glucagon and digestive enzyme secretion, amylin regulates nutrient appearance and postprandial glucose concentration. Amylin seems to be a necessary and complementary factor to insulin, which regulates the rate of nutrient disappearance. In this sense, amylin and insulin are adjunct players in the control of nutrient fluxes, and amylin's role to control feeding is a pivotal factor in this regard.
[Back to top] Modulation of Eating by Central Catecholamine
Systems
Paul
J. Wellman
The focus of the present review is the modulation of eating by the endogenous catecholamines (CA) dopamine (DA) and norepinephrine (NE). Topics addressed include pharmacological and genomic manipulations of brain CA systems and subsequent changes in ingestive behavior. DA in particular is a key component of brain reinforcement systems and feeding-associated changes in DA may play a role in the reinforcing aspects of feeding. NE has been linked to both stimulation and suppression of eating and recent evidence has linked these effects to activation of distinct adrenoceptor subtypes. Recent evidence suggests that NE systems may interact with DA systems to augment the activational effects of psychostimulant drugs, such as cocaine or amphetamine, and DA/NE interactions may play a key role in the capacity of psychostimulants to suppress eating.
[Back to top] Serotonin (5-HT) Drugs: Effects on Appetite
Expression and Use for the Treatment of Obesity
Jason
C.G. Halford, Joanne A. Harrold, Clare L. Lawton and John E. Blundell
The pivotal role of 5-HT in the control of appetite was formally proposed nearly 30 years ago. In particular endogenous hypothalamic 5-HT has been implicated in the processes of within meal satiation and the end state of post meal satiety. Of the numerous 5-HT receptor subtypes currently identified, 5-HT1B and 5-HT2C receptors are believed to mediate the 5-HT induced satiety. 5-HT drugs such as d-fenfluramine, selective serotoninergic reuptake inhibitor (SSRIs) and 5-HT2C receptor agonists have all been shown to significantly attenuate rodent body weight gain, an effect strongly associated with marked hypophagia. D-Fenfluramine, sibutramine, fluoxetine and the 5-HT2C receptor agonist mCPP have also all been shown to reduce caloric intake by modifying appetite in both lean and obese humans. Specifically, 5-HT drugs reduce appetite prior to and after the consumption of fixed caloric loads, and reduce pre meal appetite and caloric intake at ad libitum meals. Clinically significant weight loss over a year or more can be produced by both d-fenfluramine and sibutramine treatment, but apparently not by the SSRI fluoxetine. Treatment with the preferential 5-HT2C receptor agonist mCPP and the serotonin precursor 5-HTP has also been shown to produce weight loss in the obese. Issues around the actual and possible side effects of these compounds, and in the case of d-fenfluramine toxicity, have led to a search for drugs that act selectively on the CNS 5-HT receptors critical to the satiety response. Currently, a new generation of 5-HT2C selective agonists have been developed (including Ro 60-0175, Org 12962, VER-3323, BVT-933 and YM348) and at least one, ADP356, is currently undergoing clinical trials. Hopefully, such drugs will be as or even more effective at regulating appetite and controlling body weight, and will also be free of their predecessors’ side effect.
[Back to top] Cannabinoids and the Regulation of Ingestive
Behaviour
S.P.
Vickers, and G.A. Kennett
Over past centuries, Cannabis sativa (D9-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB1 and CB2 receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined.
In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB1 receptor. Conversely, experiments with selective CB1 receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes.
Such findings have led to a number of pharmaceutical companies developing selective CB1 receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo’s inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.
[Back to top] The Hypothalamus and Obesity
Peter
J. King
Obesity, a condition already at epidemic proportions in the developed world, is largely attributable to an indulgent lifestyle. Biologically we feel hunger more acutely than feeling ‘full-up’ (satiety). The discovery over a decade ago of leptin, an adiposity signal, revolutionised our understanding of hypothalamic mechanisms underpinning the central control of ingestive behaviour. The structure and function of many hypothalamic peptides (Neuropeptide Y (NPY), Melanocortins, Agouti related peptide (AGRP), Cocaine and amphetamine regulated transcript (CART), Melanin concentrating hormone (MCH), Orexins and endocannabinoids) have been characterised in rodent models. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Short-term signal hormones including Cholecystokinin (CCK), Ghrelin, Peptide YY (PYY3-36) and Glucagon-like peptide 1 (GLP-1) control meal size via pathways converging on the hypothalamus. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems among others, implicated in hypothalamic appetite regulation all provide potential “drugable” targets by which to treat obesity.