Ghrelin – The ‘Meal Initiating’ Signal
The discovery of ghrelin
Ghrelin got its name from the word 'ghre' from the Proto-Indo-European language, meaning to grow. Scientists did not go purposefully looking for a substance that stimulated appetite. Indeed the discovery of ghrelin occurred when scientists were investigating drugs that stimulated the release of growth hormone from the anterior pituitary gland. They came across some drugs that, rather then acting on the growth hormone releasing hormone receptor, were acting on an unknown receptor located in the hypothalamus and pituitary, these drugs were called growth hormone secretagogues. It was concluded that the body had a second pathway for the induction of growth hormone secretion. Ghrelin was identified as being the natural ligand for these receptors causing secretion of growth hormone in 1999 by the Japanese scientist Masayasu Kojima (see key references). During Kojima’s investigations, they found that although ghrelin’s receptors were in the brain, ghrelin was surprisingly identified in the human stomach and circulating in the blood leading to the conclusion that it was released from the stomach where it then travelled in the blood and acted on the brain.
At that time ghrelin was still considered to be primarily a stimulator of growth hormone release. This view quickly changed however when scientists discovered that injections of ghrelin into the blood caused weight gain in rodents resulting from an increase in fat tissue caused by increased food intake and a decrease in fat metabolism. This occurred independently of ghrelin’s role in stimulating growth hormone release (Tschoep et al, 2000).
Ghrelin's role as a stimulator of appetite was established in animals and so it was transferred to the clinics for its role in humans to be investigated. It was found that blood concentrations of ghrelin fluctuate throughout the day, rising before a meal and then decreasing again upon consumption of a meal (Cummings et al, 2001). More compelling evidence for ghrelin’s role in stimulating hunger in humans is that after injecting ghrelin into the blood and allowing people to consume as much as they please from a buffet, a 30% increase in food intake has been found to occur.
Figure 1: Ghrelin concentration in the blood fluctuates throughout the day, rising before a meal and then decreasing upon consumption (Adapted from Cummings et al, (2001))
It is now established that ghrelin is a peripheral signal from the stomach that is secreted upon hunger. Ghrelin travels in the blood to the brain where it activates neurones in the hypothalamus and stimulates eating. Satiety signals will then feedback to the stomach through vagal afferents and decrease the urge to eat.
Figure 2: Ghrelin secretion and the feedback mechanism
Ghrelin as an anti-obesity drug
One of the reasons that some people find dieting so difficult to maintain is that when dieting the body will produce ghrelin in response to hunger, thus stimulating eating and fat retention. Anti-obesity drugs usually act by being agonists or antagonists of receptors involved in appetite. Therefore when the drug is taken continuously, weight is reduced but upon stopping the weight may well go back on. Scientists have recently identified a possible anti-obesity drug using a vaccine against ghrelin that may provide a one-off permanent treatment for obesity. The idea of immunising against potentially naturally produced substances has been named ‘immunopharmacotherapy’. It was first used on drug users, producing an immune reaction against the drug of abuse which sequestered the drug before it could act on its target receptors. This showed promising results in rats and is currently in human clinical trials. After injecting rats with a vaccine against ghrelin, the rats ate the same as their controls but accumulated less body fat and weight (see key references).
Where does it act & how does it exert its effects
Receptors for ghrelin have been found on NPY neurones in the hypothalamic arcuate nucleus, a major brain area involved in the control of appetite. The NPY neurones are potent stimulators of appetite and upon activation by ghrelin they inhibit the POMC neurones by releasing the inhibitory neurotransmitter GABA which inhibits the release of alpha MSH, an inhibitor of appetite. Ghrelin also activates the release of AgRP which is an antagonist of the alpha MSH receptors MC3 and MC4, blocking alpha MSH from activating its receptor and inhibiting appetite (see Figure 3).
Figure 3: Ghrelin inducing hunger through its actions on NPY neurones in the arcuate nucleus
Both ghrelin and leptin carry out their effects on feeding behaviour through neurones in the arcuate nucleus. This nucleus and the peptides it synthesises are vitally important for the control of appetite which leads the discussion onto the Arcuate Nucleus and the Melanocortin System.
Kojima et al (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Letters to Nature. 402 pp 656-660
Zorrilla et al (2006) Vaccination against weight gain. Proceedings of the National Academy of Sciences. 103 (35) pp13266-13231