Leptin & Ghrelin Balance

Leptin and Ghrelin Balance: An Encyclopedic Reference

1. Definition and Overview

Leptin and ghrelin are two hormones that have been recognized to have a major influence on energy balance. Together they form the principal hormonal axis governing hunger, satiety, and long-term body weight regulation. The term leptin–ghrelin balance refers to the dynamic, opposing interplay between these two signals, and the physiological or pathological states that arise when this interplay is disrupted.

Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss, whereas ghrelin is a fast-acting hormone, seemingly playing a role in meal initiation. Since the physiological response to food intake is reciprocally regulated by the interaction between leptin and ghrelin, the ratio of concentrations of these hormones could be termed as a hunger signal.

2. The Hormones: Sources, Structure, and Basic Actions

2.1 Leptin

A seminal finding in the understanding of the mechanisms leading to body weight dysregulation was the discovery of leptin — from the Greek term leptos (thin) — identified by Friedman and collaborators at The Rockefeller University in 1994. As an adipocyte-derived hormone, leptin sends signals to the medial hypothalamus regarding energy storage within the body. Circulating leptin levels are directly proportional to the amount of body fat, thereby reflecting the status of long-term energy stores.

Leptin exerts its anti-obesity action by inhibiting food intake and inducing energy expenditure. However, leptin also has many other roles within the body, such as reproduction, blood pressure, and vast effects on the immune system, all of which have an overall impact on energy metabolism and act to change the balance within the body.

Leptin, produced mainly by adipocytes, acts on the POMC and CART neurons to promote satiety, or inhibits AgRP neurons and NPY in the arcuate nucleus of the hypothalamus to decrease food intake.

2.2 Ghrelin

Ghrelin is a peptide hormone predominantly produced by the stomach. It exerts a wide range of functions including stimulating growth hormone release and regulating appetite, food intake, and glucose and lipid metabolism. Levels of ghrelin increase before meals and have a role in increasing body weight, thus earning the name "hunger hormone." The lateral area of the hypothalamus is responsible for hunger and becomes stimulated by ghrelin.

Ghrelin is produced mainly by the stomach; it stimulates NPY and AgRP neurons, which are both strong appetite stimulators, and inhibits anorexigenic POMC/CART. Intravenous infusion of ghrelin in physiological doses induces hunger and short-term increases in food intake. Its concentration almost doubles just before a meal and falls sharply after a meal.

2.3 The Interplay and Feedback Loop

Leptin inhibits ghrelin in two ways: it reduces ghrelin secretion by gastric cells and suppresses ghrelin receptors' expression in the NPY system, thereby preventing the stimulation of feeding behaviors. This effect is postulated to constitute the major feedback loop between the organs of eating and the hypothalamus, which maintains body weight. When this loop is disrupted at any point — either in terms of timing, duration, or magnitude of feedback impulse signaling — hypothalamic control of feeding is lost, resulting in obesity.

Leptin is primarily involved in long-term regulation of energy balance — it is released into the circulatory system as a function of energy stores — whereas ghrelin is a fast-acting hormone, of which the circulatory levels show clear meal-related changes. Interestingly, leptin and ghrelin functioning in the system for energy homeostasis involves several overlapping pathways.

3. Body Systems Involved

3.1 Central Nervous System / Hypothalamus

Both hormones converge on the arcuate nucleus (ARC) of the hypothalamus, which serves as the primary integration site for metabolic hormone signals. Changes in metabolic state activate the nuclear transcription machinery by increasing expression and/or activity of key transcription factors — such as cyclic AMP-responsive element-binding protein (CREB) and its phosphorylated isoform (pCREB), FOXO1, and brain-specific homeobox protein homologue (BSX) — in the arcuate nucleus, increasing mRNA expression of AgRP and NPY, which induces feeding.

Ghrelin also acts on brain reward circuitry beyond the hypothalamus. Ghrelin acts not only on homeostatic hypothalamic-brainstem circuits that regulate energy balance but also on systems involved in learning and motivation, notably the ventral tegmental area (VTA), striatum, and hippocampus, to influence food cue reactivity. More specifically, ghrelin may increase the motivational salience of food cues by stimulating dopaminergic neurons in the VTA, where growth hormone secretagogue receptors (GHSR) are also found.

3.2 Adipose Tissue

Leptin is an adipokine — it is secreted in proportion to fat mass. Leptin belongs to a class of hormones known as adipocytokines, which play a role in regulating energy metabolism. In states of expanding fat mass, leptin output rises, theoretically increasing satiety signals; however, this feedback is impaired in obesity.

3.3 Gastrointestinal Tract

Ghrelin is primarily secreted by specialized X/A-like cells (P/D1 cells) of the gastric fundus. Studies have shown that gastric leptin secretion also responds to the intake of certain macronutrients, thereby activating mechanisms that may lead to peripheral leptin resistance and be critical early points in the pathophysiology of obesity. This evidence considers the relevant role of gastric leptin in the delivery of macronutrients from the intestine into the bloodstream and the regulation of food intake.

3.4 Cardiovascular System

Ghrelin and leptin also participate in the homeostasis of the cardiovascular system. Ghrelin operates as a cardioprotective factor, with increased circulating acylated ghrelin concentrations in patients with left ventricular hypertrophy (LVH) causally related to LV remodeling during progression to LVH. Additionally, leptin induces vasodilation by inducible NO synthase (iNOS) expression in the vascular wall.

3.5 Endocrine Interactions: Insulin and Cortisol

The pre- and postprandial ghrelin fluctuations inversely correlate with those of insulin; when insulin concentrations rise after meal intake, ghrelin concentrations fall. Ghrelin administration decreases insulin sensitivity, limits insulin secretion, elevates blood cortisol, and stimulates the release of glucagon, somatostatin, and growth hormone, among other known regulatory actions that may help explain its ability to raise glucose levels.

4. Dysregulation: Leptin Resistance and Ghrelin Resistance

4.1 Leptin Resistance

A lack of biological response despite elevated leptin levels — known as leptin resistance — is observed in individuals with excess body weight and represents a significant challenge. Obese patients and mice display high levels of circulating leptin and do not respond to leptin treatment, a condition known as leptin resistance, with underlying mechanisms that have not yet been fully elucidated.

One established pathway through which diet promotes leptin resistance involves blood lipids. Dietary sugar and saturated fats elevate plasma triglycerides, which in turn may trigger the onset of leptin resistance by inducing resistance to leptin transport at the blood–brain barrier.

Molecular mediators have also been identified. BDNF translation of the physiological 3'UTR of BDNF mRNA is enhanced by leptin. Leptin resistance occurs when this 3'UTR of BDNF mRNA is abnormally truncated, leading to severe hyperphagic obesity. HDAC5 is a critical mediator of leptin signaling and energy balance, and inhibition of its expression, or loss of function, impairs leptin sensitivity and increases body weight and food intake.

4.2 Ghrelin Resistance

The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. An emerging view is that during diet-induced obesity, stomach cells secrete less ghrelin, resulting in a state of central ghrelin resistance. Alternatively, diet-induced weight reduction can reverse ghrelin resistance, which is a defence mechanism to maintain a higher body weight set-point established during periods of food availability, maximizing energy reserves during periods of food scarcity.

4.3 The Leptin/Ghrelin Ratio as a Clinical Marker

A low leptin/ghrelin (L/G) ratio has been considered as a clinical biomarker for predicting better metabolic adaptation and increased weight loss after dietary intervention in obese women, and subsequent weight maintenance after intervention in obese subjects. This ratio has been described to decrease in type 2 diabetes patients who experienced an improvement in insulin sensitivity.

5. Contributing and Associated Factors

5.1 Obesity and Adiposity

In obese subjects, the circulating level of the anorexigenic hormone leptin is increased, whereas, surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant. This paradox — high leptin, low ghrelin, yet persistent hunger — is central to the pathophysiology of obesity-associated hormonal imbalance. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity.

5.2 Type 2 Diabetes and Insulin Resistance

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. In recent years, there has been growing interest in the role of hunger and satiety hormones such as ghrelin and leptin in the development and progression of T2DM. Recent evidence indicates that an insufficient sleep duration, with an effect on leptin metabolism, may promote the development of type 2 diabetes through increased hunger, food intake, and weight gain. Furthermore, leptin dysregulation contributes to decreased insulin secretion and sensitivity, increased insulin resistance and inflammation, and consequently an increased risk of diabetes mellitus.

5.3 Chronic Stress and the HPA Axis

Stress stimulates the release of hormones and peptides including leptin, ghrelin, and neuropeptide Y, all of which play key roles in appetite regulation and energy balance. Individuals with higher baseline total ghrelin had significantly higher food cravings at 6 months (p=0.04). Furthermore, higher cortisol, insulin, and chronic stress were each predictive of greater future weight gain. These results suggest that ghrelin plays a role in increased food cravings and reward-driven eating behaviors.

Prolonged cortisol and catecholamine release contributes to insulin resistance, visceral adiposity, and systemic inflammation, while stress-induced behavioral changes, such as poor diet and physical inactivity, exacerbate metabolic disturbances.

5.4 Sleep Duration and Quality

The relationship between sleep and appetite hormones has been studied extensively. A landmark randomized crossover clinical study at the University of Chicago tested 12 healthy men under controlled conditions of caloric intake and physical activity: sleep restriction was associated with average reductions in the anorexigenic hormone leptin (decrease, 18%; P = 0.04) and elevations in the orexigenic factor ghrelin.

A 2022 laboratory study further confirmed these findings: acute sleep deprivation reduces blood concentrations of the satiety hormone leptin, and with increased blood concentrations of ghrelin and adiponectin, such endocrine changes may facilitate weight gain if persisting over extended periods of sleep loss.

However, evidence is not entirely uniform. A 2024 systematic review and meta-analysis of six RCTs involving 141 participants found: no significant changes in ghrelin (SMD: −0.27, 95% CI: −1.00, 0.46, p = 0.4712) or leptin levels following sleep deprivation, contrary to prior studies suggesting a link between sleep loss and altered hunger hormones. The authors note significant heterogeneity across included studies, indicating that the evidence remains mixed and further large-scale studies are needed.

5.5 Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women and may involve an impairment in physiologic regulation of leptin and ghrelin. PCOS women have higher levels of serum leptin, insulin, testosterone, and luteinizing hormone (LH), whereas sex hormone-binding globulin (SHBG) is lower.

5.6 Reward Pathways and Food Addiction

The orexigenic 28-amino-acid peptide hormone ghrelin, mostly synthesized in times of stress and hunger in the stomach, and the adipokine leptin are both involved in the brain's reward circuits. Ghrelin promotes food intake especially of highly palatable foods via interaction with the brain's reward system, and increasing evidence strongly suggests that it is involved in the pathogenesis of substance-related addictive disorders, especially alcohol dependence.

6. Dietary Factors

6.1 Macronutrient Composition

Despite heterogeneity in methods to evaluate leptin resistance and its association with diet, several animal and human studies demonstrate how particular macronutrient patterns correlate to circulating leptin levels and other indicators of leptin desensitization.

Regarding dietary fat: dietary sugar and saturated fats elevate plasma triglycerides, which in turn may trigger the onset of leptin resistance by inducing resistance to leptin transport at the blood–brain barrier. A cross-sectional study of 165 overweight and obese postmenopausal women found that the relationship between habitual macronutrient intake in both leptin and ghrelin concentrations appeared to be more pronounced among women with higher insulin levels. Future studies examining associations of dietary composition with plasma ghrelin and leptin should take into account the potential role of insulin. These findings provide an initial step towards determining if there is a relationship between sustained palatable food intake among humans and a hormonal profile that could foster weight gain.

6.2 High-Protein Diets

Protein has been among the most studied macronutrients in relation to appetite hormone modulation. A study published in the American Journal of Clinical Nutrition placed 19 subjects sequentially on controlled diet phases: satiety was markedly increased with the isocaloric high-protein diet despite an unchanged leptin AUC. Mean spontaneous energy intake decreased by 441 ± 63 kcal/d, body weight decreased by 4.9 ± 0.5 kg, and fat mass decreased by 3.7 ± 0.4 kg with the ad libitum, high-protein diet, despite a significantly decreased leptin AUC and increased ghrelin AUC. The authors interpreted this to suggest that satiety-promoting effects of protein operate through mechanisms beyond simple leptin or ghrelin modulation.

A large systematic review and meta-analysis of 49 acute-intervention studies and 19 long-term studies confirmed: in acute interventions, protein decreased hunger, desire to eat, and prospective food consumption, and increased fullness and satiety. There was also a decrease in ghrelin (−20 pg/ml, P<0.001) and increase in cholecystokinin and GLP-1, but no change in gastric inhibitory polypeptide and peptide YY. Appetite markers were affected by protein doses <35 g, but ghrelin, cholecystokinin, and GLP-1 changed significantly after doses ≥35 g. Long-term ingestion of protein did not affect these outcomes, except for GLP-1, which showed a significant decrease.

7. Lifestyle Factors

7.1 Physical Exercise

Acute physical activity can modulate appetite through alterations in the levels of appetite-regulating hormones such as ghrelin, PYY, and GLP-1. A systematic review of 80 studies published in Sports Medicine found that: despite a heterogeneity of studies and a variability of the findings, the review suggests that acute exercise suppresses acyl ghrelin production regardless of the participants and the exercise characteristics. Long- and very long-term exercise training programs mostly resulted in increased total and des-acyl ghrelin production.

Regarding leptin specifically, a meta-analysis of RCTs in prediabetic and diabetic individuals found that exercise increases adiponectin and reduces leptin levels in prediabetic and diabetic individuals. However, the direction of these changes appears to depend on exercise type, duration, intensity, and participants' body weight status.

7.2 Chronic Stress Reduction

Ghrelin plays a role in increased food cravings and reward-driven eating behaviors. Studies are needed that examine the utility of stress reduction methods for normalizing disrupted cortisol responses and preventing future weight gain.

8. Nutrients, Herbs, and Natural Ingredients

8.1 Omega-3 Fatty Acids

Scientific Evidence (Human/Clinical Studies):

A review exploring animal and human data relating to the effects of omega-3 fatty acids (marine lipids) on adiponectin and leptin found that current evidence suggests a positive, dose-dependent relationship between omega-3 fatty acid intake and circulating levels of adiponectin. In obese subjects, this may translate into a reduced risk of developing cardiovascular disease, metabolic syndrome, and diabetes. In non-obese subjects, omega-3 is observed to decrease circulating levels of leptin; however, omega-3-associated increases in leptin levels have been observed in obese subjects. The reviewers note that evidence is primarily from animal studies, with human data more limited and heterogeneous. Effects on ghrelin specifically were not well characterized.

8.2 Dietary Fiber

Scientific Evidence:

Dietary fiber is considered relevant to leptin–ghrelin balance primarily through its effects on gastric emptying, postprandial glucose response, and gut microbiota composition, all of which can influence the secretion of appetite-regulating hormones. Several animal and human studies demonstrate how particular macronutrient patterns — including fiber content — correlate to circulating leptin levels and other indicators of leptin desensitization. Furthermore, studies have shown that gastric leptin secretion responds to the intake of certain macronutrients, thereby activating mechanisms that may lead to peripheral leptin resistance. Direct clinical trials isolating fiber supplementation on leptin and ghrelin remain limited and the evidence is preliminary.

8.3 Zinc

Scientific Evidence (Human Study):

A double-blind randomized trial examined the effects of 8-week zinc supplementation (50 mg/day) on leptin levels and vitamin D status in 51 postmenopausal women aged 44–76 years. Both intake and plasma zinc levels were inversely correlated to serum leptin levels (p = 0.044 and p = 0.033, respectively). Zinc supplementation improved vitamin D3 status and was associated with low leptin levels in the postmenopausal women of the study. The trial was small (n=51), limited to postmenopausal women, and the finding requires replication in larger and more diverse populations. The relationship between zinc status and ghrelin is less well characterized in the clinical literature.

8.4 Vitamin D

Scientific Evidence (Human Study):

A 2024 study investigated the effects of weekly vitamin D3 supplementation (50,000 IU for 3 months) on serum ghrelin and leptin in 40 patients with major depressive disorder (MDD) compared to 32 healthy controls. After supplementation, MDD patients showed improvements in their symptoms correlated with an increase in serum vitamin D and ghrelin concentrations. In contrast, vitamin D3 supplementation did not alter the levels of serum leptin. This study is preliminary, conducted in a clinical MDD population only, and the findings cannot be generalized to healthy adults. The authors note it is to their knowledge the first study of this specific question, underscoring the lack of broader evidence.

8.5 High-Quality Protein Sources

Scientific Evidence:

As detailed in Section 6.2, high-protein dietary intake has robust evidence for acutely reducing ghrelin levels. Results of the meta-analysis showed that acute ingestion of protein suppresses appetite and decreases ghrelin. This effect appears to require doses ≥35 g of protein per meal to reach statistical significance for ghrelin specifically. Evidence for differential effects based on protein source (e.g., animal vs. plant) remains limited.

8.6 Traditional Uses (Herbs and Botanicals)

A number of plants have traditional histories in the management of hunger, satiety, or metabolic balance. It is critical to note that the following reflects historically documented uses in folk or traditional medicine systems; the available peer-reviewed scientific evidence specifically on leptin and/or ghrelin modulation for these herbs is either very limited, preliminary, or absent at the time of writing:

• Gymnema sylvestre (Gurmar): Used in Ayurvedic medicine for centuries to reduce the perception of sweetness and manage blood sugar. Modern research has focused primarily on its effects on glucose metabolism and insulin sensitivity rather than on leptin or ghrelin directly. Controlled human trials specifically on leptin/ghrelin are lacking.
• Berberine (from Berberis spp.): Used in Traditional Chinese Medicine and Ayurveda for metabolic and gastrointestinal conditions. Emerging preclinical evidence suggests effects on adipose tissue and energy metabolism, but well-designed human trials specifically examining leptin and ghrelin endpoints are limited.
• Fenugreek (Trigonella foenum-graecum): Traditionally used in Mediterranean, South Asian, and Middle Eastern systems for digestive support and as a galactagogue. Its soluble fiber content has been associated with reduced postprandial glucose responses, which could indirectly influence ghrelin secretion, but direct evidence on leptin/ghrelin in humans is sparse.

No WHO monographs, ESCOP monographs, or EMA/EFSA assessments specifically reference leptin or ghrelin modulation as an established indication for these or other herbal medicinal products as of the available literature. Claims in this area remain investigational.

9. The Leptin–Ghrelin Axis in Context: Weight Loss and Metabolic Adaptation

Recent work suggests that leptin plays a more important role in the maintenance of weight loss than weight loss per se, and ghrelin increases appetite, adjusts energy balance, and enhances the release of growth hormone from the pituitary gland.

After caloric restriction and weight loss, compensatory hormonal changes occur. Spontaneous energy intake decreases with a high-protein, ad libitum diet, despite a significantly decreased leptin AUC and increased ghrelin AUC — a finding that suggests the body adapts by driving hunger signaling upward when fat mass declines, making sustained weight maintenance biologically challenging.

Leptin replacement dramatically reduces body weight and fat and reverses metabolic abnormalities in individuals with congenital leptin deficiency. In subjects with congenital or acquired lipoatrophy, leptin treatment improves several metabolic parameters including insulin sensitivity, dyslipidemia, and hepatic steatosis. In contrast, the common forms of obesity and type 2 diabetes are accompanied by leptin resistance. A combination therapy of leptin and leptin sensitizers has been suggested to overcome leptin resistance.

10. Evidence Gaps and Research Limitations

The manner in which both the leptin and ghrelin systems contribute to the development or maintenance of obesity is as yet not clear. Several important limitations characterize the current body of research:

• Most studies have measured only acylated ghrelin, limiting the ability to draw comprehensive conclusions about total ghrelin dynamics.
• Many nutritional intervention studies are small, short in duration, and conducted in specific populations (e.g., postmenopausal women, patients with PCOS or MDD), limiting generalizability.
• More studies are needed to better clarify the effects of dietary macronutrients on serum leptin and ghrelin.
• The mechanism linking short sleep to increased BMI, potentially through disruptions in appetite-regulating hormones, remains under investigation with conflicting results across studies.
• Evidence for herbal and botanical interventions specifically targeting the leptin–ghrelin axis in humans is largely absent from the high-quality literature, with most available data derived from animal or in vitro models.

References

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• A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight — American Journal of Clinical Nutrition
• Effect of short- and long-term protein consumption on appetite and appetite-regulating gastrointestinal hormones — PubMed
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• Omega-3 fatty acids: a review of the effects on adiponectin and leptin and potential implications for obesity management — PubMed
• Effectiveness of eight-week zinc supplementation on vitamin D3 status and leptin levels in postmenopausal women: a double-blind randomized trial — ScienceDirect
• Serum Ghrelin and Leptin Concentrations in Patients with Major Depressive Disorder before and after Supplementation with Vitamin D3 — Depression and Anxiety (2024)
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