The appetite is the desire to eat food, felt as hunger. It exists in all higher lifeforms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Dysregulation of appetite contributes to anorexia nervosa and cachexia on one side, and obesity on the other side of the spectrum.

Regulation

The regulation of appetite has been the subject of much research in the last decade. Breakthroughs included the discovery, in 1995, of leptin, a hormone that appeared to provide negative feedback. Later studies showed that appetite regulation is an immensely complex process involving the gastrointestinal tract, many hormones, and both the central and autonomic nervous systems.

Effector

The hypothalamus, a part of the brain, is the main regulatory organ for appetite. The neurones that regulate appetite appear to be mainly serotinergic, although neuropeptide Y (NPY) and Agouti-related peptide (AGRP) also play a vital role. Hypothalamocortical and hypothalamolimbic projections contribute to the awareness of hunger, and the somatic processes controlled by the hypothalamus include vagal tone (the activity of the parasympathic autonomic nervous system), stimulation of the thyroid (thyroxine regulates the metabolic rate), the hypothalamic-pituitary-adrenal axis and a large amount of other mechanisms.

Sensor

The hypothalamus senses external stimuli mainly through a number of hormones such as leptin, ghrelin, PYY 3-36, orexin and cholecystokinin; all modify the hypothalamic response. They are produced by the digestive tract and by adipose tissue (leptin). Systemic mediators, such as tumor necrosis factor alpha (TNFα), interleukins 1 and 6 and corticotropin-releasing hormone (CRH) influence appetite negatively; this mechanism explains why ill people often eat less.

In addition, the biological clock (which is regulated by the hypothalamus) modifies hunger. Processes from other cerebral loci, such as from the limbic system and the cerebral cortex, project on the hypothalamus and modify appetite. This explains why in clinical depression and stress, energy intake can change quite drastically.

Role in disease

Dysregulation of appetite lies at the root of anorexia nervosa, bulimia nervosa and binge eating disorder. In addition, decreased response to satiety may promote development of obesity. Various hereditary forms of obesity have been traced to defects in hypothalamic signalling (such as the leptin receptor and the MSH-4 receptor).

Pharmacology

Mechanisms controlling appetite are a potential target for weight loss drugs. Early anorectics were fenfluramine and phentermine. A more recent addition is sibutramine (Reductil®, Medaria®), which increases serotonin and noradrenaline levels in the central nervous system. In addition, recent reports on recombinant PYY 3-36 suggest that this agent may contribute to weight loss by suppressing appetite.

Given the epidemic proportions of obesity in the Western world, developments in this area are expected to snowball in the near future, as dieting alone is ineffective in most obese adults.

Further reading

• Neary NM, Goldstone AP, Bloom SR. Appetite regulation: from the gut to the hypothalamus. Clin Endocrinol (Oxford) 2004;60:153-60. PMID 14725674.
• Wynne K, Stanley S, Bloom S. The gut and regulation of body weight. J Clin Endocrinol Metab 2004;89:2576–82. PMID 15181026.