What is ghrelin? The hunger hormone, explained

What is ghrelin?

Ghrelin is a peptide hormone made mainly by cells in the stomach lining. It is 28 amino acids long, it rises when the stomach is empty, and it does two things the body notices: it makes people hungrier and it tells the pituitary gland to release growth hormone.

Ghrelin is a peptide hormone, a short chain of amino acids like the ones covered in our peptide basics module, and it is secreted by the food-deprived stomach [3]. It was discovered in 1999 as the natural key to a receptor that drug chemists had already been targeting for years, the growth hormone secretagogue receptor [2].

The discovery paper describes a peptide of 28 amino acids with an unusual feature: a fatty acid attached to its third amino acid, serine 3 [1]. Without that fatty acid it does not work [1]. The authors named it from ghre, the Proto-Indo-European root of the word "grow", because the first thing it was shown to do was release growth hormone [1]. Human ghrelin differs from rat ghrelin by only two amino acids [1].

Most of it comes from the top of the stomach. Ghrelin is produced in the oxyntic glands of the gastric fundus [2], by hormone cells called X/A-like cells [2].

How ghrelin is switched on

Ghrelin only works once an enzyme called GOAT attaches an eight-carbon fatty acid, octanoate, to it. GOAT is found mainly in the stomach and intestine. Once in the body, ghrelin has a very short half-life, and in humans an enzyme called butyrylcholinesterase is the main one that inactivates it.

The fatty acid on serine 3 is the switch. Ghrelin carries octanoate, an eight-carbon fatty acid, which is required for its hormone actions [3]. The enzyme that attaches it was identified in 2008 and named GOAT, ghrelin O-acyltransferase [3]. Its messenger RNA is largely restricted to the stomach and intestine, the main ghrelin-making tissues [3].

The active, fatty-acid form is called acyl-ghrelin; the form without it is des-acyl ghrelin. Ghrelin has a very short half-life [2], and butyrylcholinesterase is the main enzyme that inactivates it in humans [2]. The peptide can, however, be engineered to last longer and behave better as a drug [2].

The same gene also encodes a second peptide, the 23 amino acid obestatin [2]. It was first reported to work against ghrelin, but several independent groups could not confirm those findings [2], so treat claims about obestatin with care.

Is ghrelin the hunger hormone?

Largely, yes. In people, ghrelin roughly doubles just before each meal and falls within an hour of eating, and a ghrelin infusion made every volunteer in one trial eat more, 28% on average. But mice that cannot make ghrelin eat normally, so it is a strong hunger signal, not the only one.

The nickname comes from two early human studies. In the first, researchers drew blood 38 times over 24 hours from 10 healthy people eating on a fixed schedule [4]. Plasma ghrelin increased nearly twofold immediately before each meal and fell to its low point within 1 hour after eating, the mirror image of insulin [4].

In the second, nine healthy volunteers received an intravenous ghrelin infusion or saline in a randomised, double-blind crossover study [5]. On ghrelin, every one of them ate more from a free-choice buffet, a mean increase of 28% [5]. The authors called ghrelin the first circulating hormone demonstrated to stimulate food intake in humans [5]. Later work found the same: ghrelin given into the bloodstream reliably induces hunger and increases food intake in lean, obese, healthy and malnourished people [2].

The picture is less simple than the nickname. Mice bred without ghrelin show no significant change in how much they eat, which, in the words of a review co-written by dozens of ghrelin researchers, does not support ghrelin as an essential meal-initiation or hunger hormone [2]. Hunger has several signals, and ghrelin is one of them rather than the only one. Several other gut hormones work the other way, as fullness signals: CCK and GLP-1, the hormone behind the drugs in our GLP-1 comparison.

Ghrelin and growth hormone

Ghrelin is the body's own key to the growth hormone secretagogue receptor. In people, a single injection or a 24-hour infusion of ghrelin releases growth hormone. Synthetic growth hormone secretagogues act on this same receptor, which was cloned in 1996, three years before ghrelin itself was found.

The receptor came before the hormone. Synthetic compounds that release growth hormone from the pituitary were made long before anyone knew what they were mimicking. In 1996, one of them, MK0677, was used to clone their receptor, GHSR1a [2], and synthetic growth hormone secretagogues and growth hormone releasing peptides were shown to act on it [2]. Three years later, ghrelin turned out to be the natural signal for that receptor [2].

In humans, a single intravenous injection or a continuous 24 h ghrelin infusion induces acute growth hormone release [2] and increases 24 h pulsatile growth hormone secretion [2]. That is why compounds built to act on this receptor are discussed in growth hormone terms.

What dieting and weight loss do to ghrelin

Dieting tends to raise it. In one study, people who lost 17% of their weight on a six-month diet had 24% more ghrelin over a day. After gastric bypass the opposite happened: levels were 77% below normal-weight controls. Ghrelin is also low in obesity, which suggests it follows overeating rather than causing it.

Weight loss causes changes in appetite and energy expenditure that promote weight regain [6], and ghrelin is one candidate for why. In a study of 13 people with obesity, a six-month diet that took off 17 percent of their initial body weight was associated with a 24 percent increase in their 24-hour ghrelin levels [6]. Gastric bypass went the other way: despite a 36 percent weight loss, ghrelin over 24 hours in the bypass group was 77 percent lower than in normal-weight controls [6], which the authors suggested may contribute to how the operation works [6].

That does not make high ghrelin the cause of obesity. Ghrelin levels are low in obesity [2], which the review reads as ghrelin being a consequence rather than a cause of overeating in those cases [2]. The striking exception is Prader-Willi syndrome, a rare genetic condition with severe obesity and very high circulating ghrelin [7]; people with it are hyperphagic, driven to eat, and have very high ghrelin levels [2].

Medicines built on the ghrelin receptor

Drugs that act on the ghrelin receptor are approved only for narrow uses. Anamorelin, approved in Japan for cancer cachexia, raised lean body mass but not grip strength in lung cancer trials. Oral macimorelin and the older pralmorelin are approved as tests for growth hormone deficiency, macimorelin by the US FDA and the European Medicines Agency.

If ghrelin drives appetite and growth hormone, a drug that mimics it could help people who are wasting away. That was the idea behind anamorelin, a ghrelin-receptor agonist. ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials at 93 sites in 19 countries, in people with advanced non-small-cell lung cancer and cachexia [8]; 484 patients enrolled in ROMANA 1 and 495 in ROMANA 2 [8]. Over 12 weeks, lean body mass rose on anamorelin compared with placebo, a median of 0.99 kg against -0.47 kg in ROMANA 1 [8]. Handgrip strength did not improve [8], which is the catch: more lean mass did not make patients measurably stronger. In January 2021, Japan approved anamorelin, sold as Adlumiz, for cancer cachexia in non-small cell lung, gastric, pancreatic and colorectal cancer [11].

The second use is diagnostic. Macimorelin is an orally active growth hormone secretagogue, and swallowing a dose then measuring the growth hormone that follows can be used to test for adult growth hormone deficiency [9]. Against the insulin tolerance test, the long-standing reference, it showed a sensitivity of 87% and a specificity of 96% [9], and the trial concluded its accuracy was comparable [9]. Those data led to its approval by the US FDA and the European Medicines Agency for diagnostic testing in adults [10]. It was not the first: the 2015 review already lists pralmorelin, another ghrelin mimetic, as approved as a diagnostic for growth hormone deficiency [2].

A third idea has not arrived. Ghrelin speeds the gut, and as of the 2015 review several trials were testing ghrelin mimetics for diabetic gastroparesis and postoperative ileus, but none had been marketed [2].

Ghrelin beyond hunger

Ghrelin also acts on the brain's reward circuits, the same ones engaged by drugs of abuse, and it affects gut movement, stomach acid, blood sugar and sleep. That breadth is why researchers now describe it as far more than a hunger hormone.

The 2015 review that pulled the field together lists actions well beyond appetite: learning and memory, gut motility and gastric acid secretion, the sleep and wake rhythm, reward seeking behavior, taste and glucose metabolism [2]. Ghrelin engages reward neurocircuits that are activated by drugs of abuse [2].

For a beginner, the useful summary is short. Ghrelin is a stomach peptide that rises before meals, turns hunger up, releases growth hormone, and climbs when people diet. The approved medicines built on its receptor so far are narrow: a cachexia drug that adds lean mass without strength, and diagnostic tests.