Ghrelin is a powerful hunger hormone—often called the “hunger signal”—produced mainly by the stomach, and to a lesser extent by the small intestine, pancreas, and brain. It plays a central role particularly in the brain by regulating food intake through the stimulation of appetite, regulating energy balance, adjusting body weight, levels of adiposity or fat deposition, glucose metabolism, the production of growth hormone (GH) and influencing gut–brain communication.
In biochemical terms, ghrelin is an endogenous ligand which interacts with receptors in various tissues including the growth hormone secretagogue receptor (GHS-R) which we discuss in the latter part of this post. It was first isolated and identified from rat stomach by Kojima et al., (1999) in relation to GH production.
There are a number of reviews on this hormone which are all worth exploring:- Kojima & Kangawa, 2005; Sato et al., 2012; Müller et al., 2015).
Quick Facts About Ghrelin
| Feature | Details |
|---|---|
| Main source | Stomach (especially the fundus) |
| Target | Hypothalamus, especially the arcuate nucleus (ARC) |
| Receptor | GHS-R1a (Ghrelin receptor) – a G-protein-coupled receptor |
| Type | Peptide hormone |
| Active form | Acyl-ghrelin (requires O-n-octanoylation to be active) |
| Opposing hormone | Leptin (signals fullness) |
The peptide is 28 amino acids and the serine 3 residue is n-octanoylated. The human version is homologous to the rat version save for 2 amino acids.
What Does Ghrelin Do?
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Stimulates Hunger
Ghrelin levels rise before meals and fall after eating. It acts on the hypothalamus to:-
Increase neuropeptide Y (NPY) and AgRP expression – both stimulate appetite.
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Encourage food-seeking behaviour.
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Regulates Meal Initiation
Ghrelin helps trigger meal initiation, coordinating with other signals like blood glucose and circadian rhythms. -
Promotes Fat Storage
It encourages adiposity by reducing fat breakdown and enhancing storage—particularly during calorie restriction or fasting. -
Modulates Reward Systems
Ghrelin can enhance the pleasure of eating by activating dopaminergic neurons in reward-related areas (e.g., ventral tegmental area), making food more desirable. -
Influences Gastric Motility & Acid Secretion
It promotes gut motility, aiding in stomach emptying and increasing acid secretion—preparing the digestive tract for incoming food. -
Interacts with Gut Taste Receptors & Microbiota
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May be modulated by gut nutrient sensors (like T1Rs and T2Rs).
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Gut microbiota composition can influence ghrelin signaling.
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Ghrelin in the Big Picture of Appetite Regulation
| Hormone | Produced by | Effect |
|---|---|---|
| Ghrelin | Stomach (before meals) | Increases hunger |
| Leptin | Fat tissue | Decreases hunger |
| PYY | Ileum/colon | Decreases appetite |
| GLP-1 | Intestine | Increases satiety |
| CCK | Duodenum | Slows gastric emptying, increases fullness |
Brain–Gut Axis: How Ghrelin Gets the Message Across
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Ghrelin acts centrally, particularly at the arcuate nucleus of the hypothalamus.
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It crosses the blood-brain barrier and also signals via the vagus nerve.
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Its action is antagonistic to leptin—where leptin says “you’ve eaten enough,” ghrelin says “feed me!”
Clinical and Research Insights
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Obesity: Ghrelin levels are often lower in obese individuals but may not drop appropriately after meals, contributing to overeating.
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Fasting: Ghrelin rises, triggering food-seeking behavior.
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Bariatric Surgery: Some procedures like gastric bypass reduce ghrelin levels, helping suppress appetite.
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Psychiatric Factors: Ghrelin may also influence stress-eating and mood-related eating patterns.
Ghrelin levels follow a diurnal (circadian-like) rhythm, fluctuating predictably over the course of the day in response to food intake, sleep, and energy needs.
Here’s a detailed look at how ghrelin behaves:
Daily Pattern of Ghrelin Secretion
| Time/Event | Ghrelin Levels | Explanation |
|---|---|---|
| Before meals | Rise (peak) | Prepares the body to eat; stimulates hunger. This rise can happen even if meals are delayed or skipped. |
| Immediately after eating | Drop sharply | Signals that food has arrived; suppresses hunger. |
| 2–3 hours after meals | Gradual return to baseline | Hunger may begin to return if no further food is consumed. |
| During the night | Low or stable | Energy requirements are low during sleep; ghrelin suppression supports rest. |
| Early morning (before breakfast) | Rising again | Prepares the body to wake and eat—helps drive appetite for breakfast. |
Approximate Ghrelin Pattern (24-Hour Cycle)
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Peaks are entrained to habitual meal times.
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Anticipatory ghrelin rises can happen even without actual eating, showing it’s not just a response to emptiness but also learned behavior (a conditioned response).
Influences on Ghrelin’s Daily Rhythm
| Factor | Effect on Ghrelin |
|---|---|
| Meal timing | Delayed meals delay ghrelin peak; regular meals lead to consistent patterns. |
| Meal composition | High-carb/protein meals suppress ghrelin more than high-fat meals. |
| Sleep | Poor or restricted sleep can increase ghrelin, increasing hunger the next day. |
| Stress | May increase or dysregulate ghrelin depending on the type and chronicity. |
| Exercise | Can suppress or delay ghrelin depending on intensity and energy expenditure. |
Interaction With Other Hormones
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Opposed by leptin, which peaks after meals and during sleep.
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Works in tandem with NPY/AgRP neurons (stimulate hunger).
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Counteracted by GLP-1, PYY, and CCK, which rise postprandially and signal satiety.
Insights: Ghrelin’s Role in Meal Anticipation
In rodents and humans, ghrelin increases even if food isn’t consumed, so long as it’s expected. This means ghrelin is part of the entrained circadian feeding loop, shaped by both biology and behavior.
Ghrelin Is The Endogenous Ligand Of The Growth Hormone Secretagogue Receptor (GHS-R)
Ghrelin is the natural (internally produced) molecule in the body that binds to and activates the GHS-R, which is a receptor responsible for stimulating growth hormone (GH) release and other physiological effects. Th GHS-R is located in the pituitary and is a typical G-protein-coupled receptor (GPCR). The regulation of the production of growth hormone (GH) is now governed by two mechanisms, by ghrelin and by hypothalamic growth-hormone-releasing hormone (GHRH).
Breaking It Down
| Term | Meaning |
|---|---|
| Ghrelin | A hormone made by the stomach that stimulates hunger and promotes growth hormone release. |
| Endogenous | Produced naturally within the body, as opposed to synthetic or externally administered. |
| Ligand | A molecule that binds to a receptor to activate or block it. |
| GHS-R (Growth Hormone Secretagogue Receptor) | A receptor in the pituitary and brain that, when activated, triggers the release of growth hormone (GH) and affects appetite and energy balance. |
So in simple terms:-
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Ghrelin is the body’s natural key (ligand) that fits into the GHS-R lock (receptor).
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When ghrelin binds to GHS-R, it activates the receptor, leading to:
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Increased growth hormone secretion from the pituitary gland
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Stimulation of appetite
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Energy conservation and fat storage
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Clinical Relevance:
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Synthetic GHSs (like ibutamoren) have been developed to mimic ghrelin and stimulate GH release.
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GHS-R is a target in aging, obesity, muscle wasting, and appetite disorders research.
References
Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., & Kangawa, K. (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402(6762), pp. 656-660 (Article).
Kojima, M., & Kangawa, K. (2005). Ghrelin: structure and function. Physiological Reviews, 85(2), pp. 495-522.
Müller, T. D., Nogueiras, R., Andermann, M. L., Andrews, Z. B., Anker, S. D., Argente, J., … & Tschöp, M. H. (2015). Ghrelin. Molecular Metabolism, 4(6), pp. 437-460.
Sato, T., Nakamura, Y., Shiimura, Y., Ohgusu, H., Kangawa, K., & Kojima, M. (2012). Structure, regulation and function of ghrelin. The Journal of Biochemistry, 151(2), pp. 119-128.
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