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Studies investigating associations between sweeteners and health yield inconsistent results, possibly due to subjective self-report dietary assessment methods.

The regulation of appetite relies on the integration of numerous episodic (meal) and tonic (energy storage) generated signals in energy regulatory centres within the central nervous system (CNS). These centers provide the pharmacological potential to modify human appetite (hunger and satiety) to increase or decrease caloric intake, or to normalize aberrant eating behavior. With regard to obesity, the satiety enhancing anti‐obesity drug sibutramine has proved effective at reducing body weight. Additionally, the endocannabinoid CB1antagonist rimonabant has recently been approved for use in Europe (but not in the US). A 5‐HT2Cagonist lorcaserin is also currently undergoing large‐scale clinical trials, but the effect of the drug on human appetite is unknown as yet. Appetite enhancing drugs such as magestrol acetate and dronabiol are currently used to promote weight gain. Finally, sibutramine, selective serotonergic reuptake inhibitors such as fluoxetine and some anti‐epileptic drugs have all been used to normalise aberrant eating behaviour. All these drugs act by modifying the expression of human appetite. An assessment of a drug's effectson caloric intake and feelings of hunger and satiety is necessary before they can be considered for clinical use. © 2008 Wiley‐Liss, Inc. Dev Disabil Res Rev 2008;14:158–164.

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.

The current obesity pandemic imposes a major global disease burden. Levels of non-communicable diseases such as type 2 diabetes, cardiovascular disease and some cancers will continue to rise unless an effective approach to treat obesity is found. Sustained weight loss of between 5-10% in the obese, by various means, confers marked health benefits. The currently available pharmacotherapies, orlistat and sibutramine, can induce weight loss of between 5-10% over 2 years or more. In trials, orlistat and sibutramine induced weight loss tends to be only between 2-4 kg greater than that produced by placebo control. However, this additional placebo subtracted weight loss produces marked additional improvements in diabetes and cardiovascular risk factors. Moreover, in the 4 year long XENDOS trial, the modest placebo subtracted weight loss produced by orlistat (2.8 kg) reduced the incidence of diabetes by over a third in those with normal glucose tolerance, and by nearly half in those with impaired glucose tolerance. Despite this, prescription sales of sibutramine in the US have apparently remained static and those of orlistat have fallen, with the drug now entering the global over-the-counter medication market. Recent data on potential anti-obesity drugs currently under going phase III trials, such as Rimonabant and Topiramate, demonstrate these drugs produce greater and more prolonged weight loss. Wider use of pharmacotherapy and enhanced efficacy for the next generation of anti-obesity drugs certainly promise to reduce obesity related illness if not halt the rise in obesity per se.

The discovery of the adiposity signal leptin a decade ago revolutionised our understanding of the hypothalamic mechanisms underpinning the central control of ingestive behaviour. Subsequently, the structure and function of various hypothalamic peptide systems (Neuropeptide Y (NPY), Orexins, Melanocortins, Cocaine and Amphetamine Regulating Transcript (CART), Galanin / Galanin Like Peptides (GALP) and endocannabinoids) have been characterised in detail in rodent models. The therapeutic benefit of targeting these systems remains to be discovered. More is becoming known about the pharmacological potential of peripheral, meal-induced, episodic endogenous peptides. Hormones such as Cholecystokinin (CCK), Gastrin Releasing Peptides (GRP), Glucagon- Like Peptide 1 (GLP-1) Enterostatin, Amylin, Peptide YY (PYY) and Ghrelin are released prior to, during and / or after a meal, controlling intake and subjective feelings of appetite (hunger and satiety). In addition, there is an expanding body of literature detailing the effects of a wide variety of drugs on human appetite and food intake. Some of these drugs act upon CNS monoamine systems such as Serotonin (5-HT), Dopamine (DA) and Noradrenaline (NA), have long been implicated in appetite regulation. Detailed examination of both the effect of agonising endogenous gut peptide systems and the effect of various monoaminergic drugs on the expression of human appetite can provide a greater understanding of mechanisms underpinning normal appetite regulation. However, such an understanding must be based on knowledge of the effect of the treatment on meal size, eating rate, meal pattern, food choice and the subjective experience of appetite flux (hunger and satiety), and not just food intake.

The escalating pandemic of obesity has generated demand for a new generation of novel anti-obesity agents. Over the past 8 years numerous systems within the CNS critical to the expression of appetite and energy regulation have been revealed. With increasing knowledge we seem tantalisingly close to producing an unprecedented range of anorectic agents capable of inducing sustained clinical weight loss. However, it remains essential to establish that any test compound reduces food intake by selectively acting on the endogenous appetite system (or by inducing nausea or malaise). Only drugs (agonist or antagonist) that modify the daily flux of appetite, for instance enhancing within meal satiation and strengthening post meal satiety, can be considered as appetite suppressants with clinical potential. Systems of interest include peripheral factors released episodically prior to, during and after the consumption of food, many of which have been shown to have receptors within the Central Nervous System (CNS). These include Glucagon-Like Peptide (GLP)-1, Cholecystokinin (CCK), Gastrin Releasing Peptides (GRP), Enterostatin, Amylin, Peptide YY (PYY) and most recently Ghrelin. The identification of the hormone leptin (the ob protein), a key signal linking adipose tissue status with key CNS regulatory circuits, was arguably the key event in the current revolution in appetite research. Leptin itself may be one of a much larger class of peripheral tonic signals, with receptors within the CNS, informing the brain of the body's energy status and providing a second set of target systems. Collectively, these episodic and tonic signals appear to be integrated in key CNS circuits containing monoamine neurotransmitters (Serotonin - 5-HT, Nor-Adrenaline - NA, and Dopamine - DA) and numerous neuropeptides (Melanocortins, Neuropeptide Y - NPY, Orexins, Cocaine and Amphetamine Regulating Transcript - CART, Agouti Related Peptide - AgRP and Galanin) all of which could be selectively targeted to reduce food intake and induce weight loss. Food intake can also be adjusted by drugs such as the cannabiniods acting upon the hedonic components of eating behaviour. However, any drug targeting the aforementioned systems must produce changes in feeding behaviour such as meal patterns and food choice consistent with a selective action on appetite. Ultimately in humans, this will be expressed in changes in meal size, reduced snacking and possibly a selective reduction in the intake of calorie dense high fat foods.