Appetite is the desire to eat and this usually initiates food intake. Following a meal, satiation occurs. This depends on gastric and duodenal distension and the release of many substances peripherally and centrally.

Following a meal, cholecystokinin (CCK), bombesin, glucagon-like peptide 1 (GLP1), enterostatin, and somatostatin are released from the small intestine, and glucagon and insulin from the pancreas. All of these hormones have been implicated in the control of satiety. Centrally, the hypothalamus – particularly the lateral hypothalamic area, and paraventricular and arcuate nuclei – plays a key role in integrating signals involved in appetite and bodyweight regulation. There are two main pathways in the arcuate nucleus:

• The central appetite-stimulating (orexogenic) pathway in the ventromedial part of the arcuate nucleus, which expresses NPY (neuropeptide Y) and AgRP (agouti-related protein). Animal studies suggest that this pathway also decreases energy expenditure.
• The central appetite-suppressing (anorexogenic pathway, or leptin-melanocortin pathway) in the dorsolateral part of the arcuate nucleus, which expresses POMC/CART (pro-opiomelanocortin/cocaine-and-amfetamine-regulated transcript). In this pathway, α-MSH (α-melanocyte-stimulating hormone), formed by cleavage of POMC by PC1 (prohormone convertase), exerts its appetite-suppressing effect via the Mc4R (melanocortin-4 receptors) in areas of the brain that regulate food intake and autonomic activity. Animal studies suggest that this pathway also increases energy expenditure.

These pathways interact with each other and feed into the lateral hypothalamus, which communicates with other parts of the brain, and influence the autonomic nervous system and ingestive behaviour. These central pathways are in turn influenced by a variety of peripheral signals which can also be classified as appetite stimulating or appetite suppressing.

• Peripheral appetite-suppressing: Leptin and insulin act centrally to activate the appetite-suppressing pathway (whilst also inhibiting the appetite-stimulating pathway). Since these hormones circulate in proportion to adipose tissue mass, they can be regarded as long-term signals, although they probably also modulate short-term signals (insulin also responds acutely to meal ingestion). Peptide YY (PYY) is produced by the L cells of the large bowel and distal small bowel in proportion to the energy ingested. The
  release of this rapidly responsive (short-acting) signal begins shortly after food intake, suggesting that the initial response involves neural pathways, before ingested nutrients reach the site of PYY production. PYY is thought to reduce appetite, at least partly through inhibition of the appetite-stimulating pathway (NPY/AgRP-expressing neurones).
• Peripheral appetite-stimulating: Ghrelin is a 28-amino-acetylated peptide produced by the oxyntic cells of the fundus of the stomach. It is the first known gastrointestinal tract peptide that stimulates appetite by activating the central appetite-stimulating pathway. The circulatory concentration is high before a meal and is reduced rapidly by ingestion of a meal or glucose (cf. peptide YY, which increases after a meal). It may also act as a long-term signal, as its circulating concentration in weight-stable individuals is inversely related to body mass index over a wide range (cf. insulin and leptin which are positively related to BMI (see below)). It is also increased in several situations in which there is a negative energy balance, e.g. long-term exercise, very low-calorie diets, anorexia nervosa and both cancer and cardiac cachexia (an exception is vertical banded gastric bypass surgery, where its concentration is low rather than high).

The single gene mutations affecting this pathway in humans, e.g. leptin, leptin receptor, POMC, Mc4R, PC1, and SIM1, are rare and recessive, with the exception of the Mc4R, which is common and dominant with incomplete penetrance. It appears that the Mc4R mutation accounts for 2-6% of human obesity. Affected individuals are obese without disturbances in pituitary function or resting energy expenditure, although children tend to be tall. However, these mutations are of little significance as obesity is predominantly polygenetic in origin (the human obesity gene map has already identified several hundreds of candidate genes).

The recent obesity epidemic is mainly due to behaviour and lifestyle changes (although it may be that individuals with certain genes are affected more than others) with a trebling in the prevalence of obesity in the UK over the last 25 years.

The control of appetite is extremely complex. For example, if one considers only one signal, i.e. leptin, there can be leptin resistance where obese individuals have high circulating leptin but with no reduction of appetite. Alternatively in starvation there may be inappropriate correlation between leptin release and loss of adipose tissue. It is known that cytokines, such as TNF and IL-2, which are elevated in a wide range of inflammatory and traumatic conditions, also suppress appetite, although the exact pathways involved are not entirely clear. Finally, there are a range of transmitters in the central nervous system, some of which appear to inhibit appetite (dopamine, serotonin, γ-aminobutyric acid) and others which stimulate appetite (e.g. opioids).