Current Drug Targets - Volume 5, Issue 3, 2004

Over the last decade, understanding of the circuits and molecules involved in the regulation of energy balance has expanded dramatically. A complex system has evolved which allows the brain to read, interpret and integrate a wide range of signals and to elicit appropriate changes in food intake and energy expenditure as a result of the information. A series of shortterm signals derived from the gastrointestinal tract, such as cholecystokinin, govern meal size. Other hormones e.g. insulin and leptin, and circulating nutrients offer long-term regulation. These signals act at a variety of central nervous system sites, but the majority of pathways converge on the hypothalamus, which itself contains numerous peptides and neurotransmitters that influence feeding and energy expenditure. Mutations in key components of these circuits underlie some of the syndromes of genetic obesity in rodents, but are responsible for only a small percentage of human obesity - which is largely attributed to an adverse lifestyle. However, various abnormalities have been identified in dietary-obese rodents, which is the closest model to 'common' human obesity. The relevance of these to energy homeostasis in humans remains uncertain, but some are likely to emerge as therapeutic targets for the treatment of both obesity and eating disorders.

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.

Adipose tissue plays an active role in energy balance because it is not only a lipid storing and mobilizing tissue but consists of functionally specialized tissues able to produce heat (in brown adipose tissue) and to produce or release a vast number of so called adipokines or adipocytokines. These consist of polypeptides but also non-protein factors and are metabolically active molecules belonging to different functional categories like immunity (complement factors, haptoglobin), endocrine function (leptin, sex steroids, various growth factors), metabolic function (fatty acids, adiponectin, resistin), and cardiovascular function (angiotensinogen, PAI-1). Recent advances using genomic and proteomic approaches have identified numerous new adipocyte secreted factors whose function remain to be established. Too little as well as too much adipose tissue leads to metabolic disturbances like insulin resistance. Visceral obesity is especially strongly correlated with the development of diabetes, hypertension and cardio-vascular disease. Thermogenesis in brown adipose tissue is a means to dissipate excess energy, but in adult humans brown fat is very scarce and probably not functional. However, human white adipose tissue contains mesenchymal stem cells, and if these could be stimulated to differentiate into brown adipocytes, increased energy expenditure in white fat could help to shift energy balance towards a more negative state.

Immune activation occurs in response to noxious stimuli such tissue injury, infection, inflammation and malignant neoplasia with the production of cytokines both in the circulation and the central nervous system (CNS). In addition to their fundamental immune functions, cytokines such as the interleukins (ILs), interferons (IFNs) and tumour necrosis factor-a also elicit significant pathophysiological effects on feeding behaviour and play prominent roles in the anorexia and cachexia syndrome often seen in chronic disease states. There is now compelling evidence that demonstrates that an important site of cytokine bioactivity is located within the hypothalamus where they appear to modulate appetite and energy homeostasis. Hypercytokinaemia has also been observed in the obese state where it has been proposed that they may play pivotal roles in mediating the detrimental components of the metabolic syndrome including insulin resistance, impaired glucose tolerance, hypertension, dyslipidaemia and increased cardiovascular risk. This review summarises these putative roles of various cytokines in the regulation of feeding in the setting of anorexia-cachexia and obesity.

Cachexia is a complex syndrome. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present article is to review the different therapeutic approaches that have been designed to fight and counteract muscle wasting in different pathological states such as cancer, AIDS and chronic heart failure.

The antipsychotic drugs (APDs) are fundamental tools in current psychiatric practice. A new generation of agents, the atypical APDs, represents an important progress in the treatment of psychotic disorders. Unfortunately, some of them induce excessive body weight gain (BWG), obesity, hyperglycemia and dyslipidemia in the following order: clozapine ≅ olanzapine > quetiapine > risperidone > ziprasidone = aripiprazole. Appetite stimulation is probably the main mechanism of BWG and this is strongly correlated with the APD affinity for H1 (histaminergic) and a1 (adrenergic) receptors. A composed ratio of the APD affinity for diverse neurotransmitters involved in food intake (FI) regulation correlates with BWG as well. Endocrine/metabolic mechanisms, such as the activation of the hypothalamus-pituitary-adrenal axis, changes in insulin sensitivity (by conventional and atypical agents), hyperprolactinemia and gonadal dysfunction (by conventional APDs and risperidone) may also be involved. Importantly, patients with schizophrenia may have a genetically-based predisposition to appetite dysregulation, insulin resistance and endocrine imbalance involving gonadal steroids. Excessive BWG must be prevented or attenuated by proper drug selection, combining or switching agents, nutritional assistance and physical exercise. Amantadine, metformin and reboxetine proved to significantly lessen APD-induced BWG. Notwithstanding this, novel strategies are necessary to treat this side effect in a clinical population particularly prone to poor compliance and under a high risk of negative drug interaction.

Binge eating disorder (BED) is a newly defined diagnostic category characterized by recurrent episodes of binge eating not followed by the inappropriate compensatory weight loss behaviors characteristic of bulimia nervosa. BED is usually associated with overweight or obesity and psychopathology. Pharmacotherapy may be a useful component of a multidimensional treatment approach. Although pharmacotherapy research in BED is still in its preliminary stages, some drugs have been shown to be promising agents. This paper reviews available pharmacological treatment studies of BED and related conditions. Currently, three main classes of drugs have been studied in double-blind, placebo controlled trials in BED: antidepressants, anti-obesity agents, and anticonvulsants. Serotonin selective reuptake inhibitors (SSRIs) are the best studied medications. Thus, fluoxetine, fluvoxamine, sertraline and citalopram have been shown to modestly but significantly reduce binge eating frequency and body weight in BED over the short term. More recently, the anti-obesity agent sibutramine and the anticonvulsant topiramate have been shown to significantly reduce binge eating behavior and body weight in BED associated with obesity. Special issues concerning current pharmacological trials and future research directions in this area are also discussed.

The pharmacological treatment options for obesity are currently very limited but the prevalence of the disease is increasing rapidly. Obesity has many serious sequelae, the most common of which is type-2-diabetes. The benefits of weight loss on health are established but the major impediment to weight loss treatments is maintenance of weight lost over the long term. The reduced- or post-obese individual undergoes physiological changes that are geared towards energy storage and weight regain. One of the physiological changes is a reduced capacity to oxidise fatty acids pushing them through pathways of triacylglycerol synthesis. In this review, some of the past drug treatments aimed at increasing energy expenditure, such as dinitrophenol and ephedrine, are discussed. Current, or nearly current therapies such as sibutramine and rimonabant are also discussed in the context of increased energy expenditure. The main part of the review focuses on future prospects with discussion around a selection of targets with potential in energy expenditure that lie in pathways with AMP-kinase at their centre and ending at the mitochondrion.

Obesity is a major health problem and as a result, it is reasonable to consider pharmacological approaches alongside approaches involving diet, physical activity and lifestyle change. The currently available drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in co-morbidity, but do not meet the often unrealistic expectations of patients or health care professionals managing obese patients. There is insufficient data on efficacy or safety of other agents to support their use. Many new pharmacological approaches are under investigation. These include gut hormones, such a peptide YY (3-36) and cholecystokinin that normally signal satiety, and centrally acting agents such a serotonin agonists, the anticonvulsants topiramate and zonisamide, cannabinoid receptor antagonists and drugs that act on other peptide neurotransmitter systems such as NPY and the melanocortins. Given the multiple pathways that influence energy balance, it is likely that therapies targeting more than one control system may be required in the future to meet the expectations and needs of patients needing to lose weight for medical reasons.