Orexins and appetite regulation

Abstract

Initial research on the functional significance of two novel hypothalamic neuropeptides, orexin-A and orexin-B, suggested an important role in appetite regulation. Since then, however, these peptides have also been shown to influence a wide range of other physiological and behavioural processes. In this paper, we review the now quite extensive literature on orexins and appetite control, and consider their additional effects within this context. Although the evidence for orexin (particularly orexin-A and the orexin-1 receptor) involvement in many aspects of ingestive physiology and behaviour is incontrovertible, central administration of orexins is also associated with increased EEG arousal and wakefulness, locomotor activity and grooming, sympathetic and HPA activity, and pain thresholds. Since the orexin system is selectively activated by signals indicating severe nutritional depletion, it would be highly adaptive for a hungry animal not only to seek sustenance but also to remain fully alert to dangers in the environment. Crucial evidence indicates that orexin-A increases food intake by delaying the onset of a behaviourally normal satiety sequence. In contrast, a selective orexin-1 receptor antagonist (SB-334867) suppresses food intake and advances the onset of a normal satiety sequence. These data suggest that orexin-1 receptors mediate the episodic signalling of satiety and appear to bridge the transition from eating to resting in the rats’ feeding-sleep cycle. The argument is developed that the diverse physiological and behavioural effects of orexins can best be understood in terms of an integrated set of reactions which function to rectify nutritional status without compromising personal survival. Indeed, many of the non-ingestive effects of orexin administration are identical to the cluster of active defences mediated via the lateral and dorsolateral columns of the midbrain periaqueductal gray matter, i.e., somatomotor activation, vigilance, tachycardia, hypertension and non-opioid analgesia. In our view, therefore, the LH orexin system is very well placed to orchestrate the diverse subsystems involved in foraging under potentially dangerous circumstances, i.e., finding and ingesting food without oneself becoming a meal for someone else.

Introduction

Obesity, defined as a body mass index (BMI) of ⩾30 kg/m², arises from a chronic net excess of energy intake over energy expenditure and is currently recognised as the largest and fastest growing public health problem in the developed world (WHO, 1998). More than 100 million people worldwide are considered obese, with recent UK statistics indicating that prevalence in both men and women has almost tripled (from c7% to c20%) in the past 20 years (Prescott-Clarke and Primatesta, 1998). The medical significance of this alarming trend is that obesity not only impairs general quality of life but also increases morbidity (e.g., Type II diabetes, ischaemic heart disease, hypertension, stroke, osteoarthritis and cancer) and leads to a 2-fold increase in the risk of premature mortality (Kopelman, 2000; Macdonald, 2000; McIntyre, 1998). Furthermore, economic surveys estimate that the direct costs of obesity account for up to 6% of annual health budgets in developed countries (Wolf and Colditz, 1998) which, in the UK, amounts to around $\text{£}$350 million p.a. As a 10 kg weight loss markedly reduces the adverse effects of obesity (WHO, 1998), there is an urgent need for the development of effective treatments for those who are already obese or who will become obese in the future (Finer, 1999).

The current prevalence of obesity reflects a dynamic interaction between societal change (i.e., low energy expenditure associated with an increasingly sedentary existence) and the ready availability of palatable foods (i.e., high energy intake associated with energy-dense foods). It is therefore unsurprising that the majority of treatment programmes have emphasised the primacy of behaviour modification through exercise and dieting. However, while such lifestyle changes can lead to successful weight loss, this is often only modest in degree and temporary in duration (Chiesi et al., 2001; Clapham et al., 2001; Macdonald, 2000). For these reasons, it has been argued that drug treatment should be an active option for those patients unable to benefit from behaviour modification programmes alone (Carpino, 2000). Nevertheless, it is pertinent to note that, largely as a result of the unsympathetic public view that sufferers are responsible for their own misfortune, scientific interest in the precise mechanisms of obesity has traditionally been relatively low on the list of research priorities. Indeed, following the withdrawal of fenfluramine/phenteramine in 1997, only three drugs are currently marketed in Europe for the treatment of obesity, mazindol (an adrenergic agonist), sibutramine (a serotonin/noradrenaline reuptake inhibitor) and orlistat (a lipase inhibitor). Unfortunately, none of these agents achieves a weight loss greater than 10–15% and serious doubts have been expressed about the sustainability of even this very modest response (Clapham et al., 2001). However, at least three factors have contributed to a significant change in attitude towards obesity among scientists, the public, regulatory authorities and the pharmaceutical industry: (i) the realisation that this disorder is in the same league as the world’s most serious diseases, (ii) the rapidly growing prevalence of obesity in the developed/developing world, and (iii) the discovery of novel brain mechanisms that regulate appetite and which present exciting opportunities for the development of novel treatment strategies (Dourish, 1999).