Leptin and ghrelin — how the hunger and satiety hormones regulate appetite

Leptin and ghrelin are two hormones with opposing effects on appetite. Leptin, secreted by adipose tissue, is a long-term satiety signal — it informs the brain about the state of the energy reserves. Ghrelin, secreted mainly by the stomach, is a short-term hunger signal — it intensifies appetite before a meal. Together they form the basis of the hormonal regulation of appetite.

This article is educational in character and constitutes a review of the published scientific literature on the endocrinology of appetite regulation. It is not medical or dietary advice. It describes hormonal mechanisms, not guidance for action. Some of the data cited come from human studies, some from models.

Leptin — the hormone of reserves and satiety

Leptin was discovered in 1994 as the product of the ob gene, and its name comes from the Greek leptos — “thin” (Zhang et al., 1994). It is a protein hormone secreted above all by white adipose tissue, in an amount roughly proportional to the mass of stored fat. The larger the fat reserves, the higher the leptin concentration.

The function of leptin is to inform the brain about the state of the long-term energy reserves. It acts as an “adipostat” signal — a system regulating the amount of adipose tissue much as a thermostat regulates temperature. When the reserves are high, high leptin signals satiety to the hypothalamus: it suppresses appetite and sustains energy expenditure. When the reserves fall (e.g. during weight loss), the leptin concentration drops sharply, and the brain reads this as a signal of deficit — it intensifies hunger and lowers expenditure.

Importantly, leptin is a stronger signal of deficit than of excess. Its fall during weight loss triggers a vigorous defensive response, whereas its rise during weight excess does not suppress appetite equally effectively — which leads directly to the phenomenon of leptin resistance.

Leptin also serves functions beyond appetite itself: it participates in the regulation of reproduction (it signals whether the energy reserves are sufficient for reproduction), the modulation of the immune system and sexual maturation. This makes it a hormone linking the body’s energy state with other physiological systems.

Particularly instructive is the contrast between rare congenital leptin deficiency and common leptin resistance. People with a genetic absence of leptin (an extremely rare mutation) experience extreme, uncontrolled hunger from childhood — and administering leptin restores normal appetite regulation and leads to the normalisation of weight. This is proof that in these cases the leptin signal works when it is present. In typical obesity the opposite is true: there is plenty of leptin, but the brain does not respond to it (Friedman and Halaas, 1998). This contrast explains why leptin did not become a treatment for common obesity.

Ghrelin — the hunger hormone

Ghrelin, discovered in 1999, is in many respects the opposite of leptin (Kojima et al., 1999). It is a peptide hormone secreted mainly by the cells of the stomach. Unlike leptin — a long-term signal — ghrelin acts in the short term, in the rhythm of meals.

The ghrelin concentration rises before a meal, peaking when the stomach is empty, and falls after eating. This makes it the main hormonal signal that initiates appetite — it is sometimes called “the hunger hormone”. Ghrelin acts on the hypothalamus, stimulating the neurons that intensify appetite, and participates in the reward signalling associated with food.

The name “ghrelin” in fact reflects its originally discovered function — it comes from the root meaning “growth hormone release”. Ghrelin is a strong, natural stimulator of growth hormone secretion, acting through the GHS-R receptor — the same one on which the peptide secretagogues studied in the context of the somatotropic axis act. Appetite regulation and growth hormone regulation thus meet in a single molecule, which neatly illustrates how the body’s metabolic pathways intertwine.

Ghrelin is also connected with body weight regulation over the longer term. In weight-loss research, the ghrelin concentration has been observed to rise after weight loss and may remain elevated — which is among the mechanisms that intensify hunger, described in the context of metabolic adaptation and the defence of body weight (Cummings et al., 2002).

Leptin and ghrelin — two opposing signals

The simplest way to frame the relationship between these hormones is as a pair of opposite sign and different time scale.

Their complementarity creates a system of appetite regulation operating over two time horizons: leptin oversees the long-term balance of reserves, ghrelin regulates the short-term rhythm of eating. Both signals meet in the hypothalamus, where they are integrated with others — a process described in a separate article on the gut–brain axis.

It is worth noting that leptin and ghrelin are only two of the many hormones that regulate appetite — alongside them act, among others, the incretins (GLP-1, GIP) and the peptide PYY, which also signals satiety after a meal. Leptin and ghrelin nonetheless stand out as the best-understood pair with opposing actions, providing a starting point for understanding the whole system.

Leptin resistance — when the signal stops getting through

One of the most important phenomena in this area is leptin resistance. Intuitively, one might expect that since leptin suppresses appetite, people with large fat reserves — and therefore a high leptin concentration — should have a weak appetite. In reality the opposite is observed: despite high leptin, the brain behaves as though its signal were weak.

Leptin resistance is precisely this state: the brain stops effectively receiving the leptin signal, despite its elevated concentration. Mechanistically this is associated, among other things, with impaired transport of leptin into the brain, disturbances of intracellular signalling in hypothalamic neurons, and chronic inflammation. The result is a weakening of leptin’s inhibitory influence on appetite, which favours the defence of a higher body weight.

Leptin resistance is described in the literature as a physiological mechanism, not as a separate disease entity “to be treated”. This description concerns the mechanism and does not constitute medical or diagnostic advice or a suggestion of any course of action.

Leptin resistance is sometimes set alongside insulin resistance as a related phenomenon of “hormone resistance” in metabolic states — with the difference that it concerns satiety signalling rather than glucose homeostasis. The mechanism of insulin resistance is expanded in a separate article.

What is important for understanding this mechanism is that leptin resistance creates a kind of feedback loop that hampers weight loss: larger fat reserves mean higher leptin, but under resistance the brain “does not see” these reserves and does not suppress appetite in proportion to their size. From the perspective of the regulatory centres, the body behaves as though the reserves were smaller than they actually are — which favours the defence of a higher body weight and hinders its spontaneous reduction. This is one of the reasons why body weight regulation is mechanistically resistant to simple interventions.

The pharmacology of satiety signals — a research direction

Since leptin and ghrelin regulate appetite, the pharmacology of these signals naturally became a subject of research into metabolism. Direct administration of leptin proved ineffective in typical obesity, precisely because of leptin resistance — which directed researchers’ attention towards other axes of satiety signalling.

The best-studied of these is the incretin axis. GLP-1 receptor agonists provide an exogenous satiety signal acting on the hypothalamus independently of leptin resistance — which is one of the mechanisms underlying their effect on appetite in clinical studies. The mechanism of the incretins is described in a separate article on GLP-1, GIP and glucagon.

Mentions of GLP-1 agonists refer to medicines used under medical supervision and to subjects of research — they are not advice or a suggestion of use. This is a review of research directions.

A second direction analysed is the central regulation of appetite through neurotransmitters — the subject of research here is, among others, tesofensine, a reuptake inhibitor that affects appetite signalling, described in a dedicated article. These substances are available in the One-Peptides catalogue solely as research reagents (semaglutide, GLP-1/GIP and related) — Research Use Only, not medicines or products for use in humans.

State of the research — an overview

Frequently asked questions

How does leptin differ from ghrelin?
Leptin is a satiety hormone secreted by adipose tissue, signalling long-term energy reserves. Ghrelin is a hunger hormone secreted mainly by the stomach, acting in the short term — it rises before a meal and falls after it. Leptin suppresses appetite, ghrelin intensifies it; together they form an opposing system of appetite regulation.

What is leptin resistance?
It is a state in which the brain stops effectively receiving the leptin signal despite its elevated concentration (proportional to large fat reserves). The result is a weakening of leptin’s inhibitory influence on appetite. Leptin resistance is described as a physiological mechanism, not a separate disease to be treated.

Why does ghrelin rise after dieting?
In weight-loss research, a rise in the ghrelin concentration has been observed, which may persist after weight loss. This is one of the mechanisms that intensify hunger after a diet, and it belongs to the physiological defence of body weight, described in the context of metabolic adaptation and the set point.

Does administering leptin help in obesity?
In typical obesity, direct administration of leptin has proved ineffective in studies, precisely because of leptin resistance — the brain does not respond to the additional signal. This directed research towards other axes of satiety signalling, including the incretin axis. This is a description of the state of the research, not a recommendation.

How do leptin and ghrelin affect body weight?
Indirectly — through the regulation of appetite and energy expenditure via the hypothalamus. Leptin sustains satiety and expenditure, ghrelin intensifies appetite. Disturbances of this signalling (e.g. leptin resistance, a rise in ghrelin after weight loss) favour the defence of a higher weight. The integration of these signals in the brain is described in the article on the gut–brain axis.

Is ghrelin connected with growth hormone?
Yes. Ghrelin was originally described as a stimulator of growth hormone secretion — it acts through the GHS-R receptor, the same one on which the peptide growth hormone secretagogues act. Appetite regulation and the regulation of the somatotropic axis thus meet in a single molecule, which illustrates the intertwining of metabolic pathways.

Why does leptin resistance hinder weight loss?
Because under resistance the brain “does not see” the actual fat reserves despite high leptin and does not suppress appetite in proportion to their size. The regulatory centres behave as though the reserves were smaller than they are — which favours the defence of a higher weight. This is a description of the mechanism, not a diagnostic criterion or guidance for action.

Summary

• Leptin is a satiety hormone from adipose tissue, signalling long-term energy reserves (the adipostat).
• Ghrelin is a hunger hormone from the stomach, acting in the short term — it rises before a meal and falls after it.
• Both signals are opposing and complementary; they meet in the hypothalamus.
• Leptin resistance is a weakening of the reception of the leptin signal despite its high concentration — a mechanism, not a separate disease.
• The pharmacology of satiety signals (the incretin axis, central appetite regulation) is a research direction — analysed scientifically, not as an intervention.

The content is educational in character and constitutes a review of the published scientific literature on the endocrinology of appetite regulation. It does not constitute medical, dietary or diagnostic advice; it does not serve to diagnose or treat any conditions, including leptin resistance. Mentions of GLP-1 agonists and other substances refer to medicines used under medical supervision and to subjects of research, and are not a recommendation. The products in the One-Peptides catalogue are chemical reagents intended solely for laboratory research (Research Use Only), not medicines or products for consumption. Decisions concerning health and body weight should be discussed with a doctor or dietitian.

Bibliography

1. Zhang Y et al. (1994). Positional cloning of the mouse obese gene and its human homologue
2. Kojima M et al. (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach
3. Cummings DE et al. (2002). Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery
4. Friedman JM, Halaas JL (1998). Leptin and the regulation of body weight in mammals
5. Klok MD, Jakobsdottir S, Drent ML (2007). The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review

Bartosz BartczakPhysiotherapist, Personal Trainer

Physiotherapist with 20 years of clinical experience, graduate of Poznan University of Medical Sciences. Founder of One Peptides and lead author of clinical-perspective content.

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