Ghrelin, often referred to as the “hunger hormone,” plays a central role in regulating appetite and energy balance. Discovered in 1999, this peptide hormone is primarily produced in the stomach, with smaller amounts released from other tissues such as the pancreas, small intestine, and brain. Ghrelin’s primary function is to stimulate appetite, promoting food intake by signaling hunger to the brain. It is intricately involved in the body’s energy homeostasis and metabolic processes.

At its core, ghrelin acts as a key regulatory factor in body weight by influencing both hunger and food intake. High ghrelin levels generally coincide with increased hunger and food cravings, contributing to weight gain and fat accumulation. In contrast, low levels of ghrelin are associated with reduced appetite. However, when the regulation of ghrelin becomes disrupted, particularly in individuals who are obese or have metabolic disorders, its ability to signal hunger can lead to overeating, fat accumulation, and an increased risk of obesity-related health issues.

Ghrelin and Its Role in Hunger Regulation

The Production of Ghrelin

Ghrelin is primarily secreted by the gastric mucosa (the lining of the stomach) but is also produced in smaller amounts by other tissues in the body. It is synthesized as a precursor protein known as preproghrelin, which is then cleaved into an active form that can bind to its receptor, known as the growth hormone secretagogue receptor (GHS-R). This receptor is found in various areas of the brain, particularly in the hypothalamus, where it plays a significant role in regulating hunger and energy expenditure.

The secretion of ghrelin follows a circadian rhythm, with levels typically peaking before meals to stimulate hunger and dropping after food intake. This mechanism helps coordinate feeding behavior, ensuring that the body seeks nourishment when energy stores are low.

Ghrelin and the Hypothalamus

Once ghrelin is secreted into the bloodstream, it travels to the hypothalamus, a region of the brain responsible for regulating appetite, thirst, and energy balance. Ghrelin specifically interacts with the arcuate nucleus of the hypothalamus, where it stimulates the release of neuropeptides that increase appetite, such as neuropeptide Y (NPY) and agouti-related peptide (AgRP). These neuropeptides act on other areas of the brain, signaling the body to seek food.

In addition to stimulating hunger, ghrelin also inhibits signals of satiety in the brain. This helps ensure that the body eats when it requires energy, especially in states of negative energy balance, such as during periods of fasting or dieting.

Ghrelin and Growth Hormone Release

Beyond its effects on appetite, ghrelin also has an important role in regulating growth hormone (GH) release from the pituitary gland. The secretion of growth hormone helps regulate body composition by promoting fat breakdown and muscle growth. This dual role of ghrelin—regulating both hunger and growth hormone—underscores its significance in maintaining overall energy balance and body weight.

How High Ghrelin Levels Lead to Increased Hunger and Cravings

The Role of Ghrelin in Hunger and Food Intake

When ghrelin levels are elevated, individuals experience heightened feelings of hunger and cravings. The increase in ghrelin levels can occur due to several factors:

  • Fasting or calorie restriction: During periods of fasting or dieting, ghrelin levels naturally rise to encourage food intake. This adaptive mechanism ensures that the body seeks energy when calorie reserves are low.
  • Sleep deprivation: Studies have shown that lack of sleep can increase ghrelin levels, which may explain why people often feel hungrier and crave higher-calorie foods after a poor night’s sleep.
  • Stress: Chronic stress has been linked to higher ghrelin levels, potentially due to the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the body’s stress response. This mechanism may drive overeating as a coping mechanism, especially with the preference for high-sugar and high-fat foods.

The Impact of Ghrelin on Cravings for High-Calorie Foods

Ghrelin not only increases hunger but also specifically enhances cravings for energy-dense, high-calorie foods, such as those rich in fats and sugars. This effect may have evolutionary significance: in times of food scarcity, the body would seek out high-calorie foods to replenish energy stores. However, in modern society, where food is abundant, the heightened desire for these calorie-dense foods can contribute to overeating and weight gain.

Additionally, ghrelin may interact with the brain’s reward system, particularly the mesolimbic pathway, which is involved in pleasure and reinforcement. High ghrelin levels may amplify the brain’s response to food stimuli, making eating more rewarding and reinforcing overeating behaviors.

Ghrelin Resistance and Its Role in Obesity

Ghrelin and Obesity

While ghrelin is typically thought to stimulate hunger, its role in obesity is more complex. In individuals with obesity, the relationship between ghrelin and weight gain may not follow the expected patterns. Despite having larger fat stores, obese individuals often exhibit higher ghrelin levels, which can lead to increased hunger and overeating.

This phenomenon is referred to as ghrelin resistance, a condition in which the body’s response to ghrelin becomes altered. In individuals who are obese, the normal feedback mechanism of ghrelin signaling may be disrupted, causing the brain to misinterpret ghrelin’s signals. As a result, the individual may experience excessive hunger, even in the presence of sufficient energy stores.

Ghrelin Resistance and the Brain’s Response to Hunger

In a normal system, after eating, ghrelin levels should decrease, signaling satiety and reducing hunger. However, in obese individuals, ghrelin levels may remain elevated, or the brain may become less responsive to decreases in ghrelin levels, leading to prolonged feelings of hunger. This contributes to an ongoing cycle of overeating, where high ghrelin levels push the individual to consume more food, thereby promoting further weight gain.

Disrupted Ghrelin Regulation in Obesity

The disrupted regulation of ghrelin in obesity is influenced by multiple factors:

  • Adiposity (fat stores): In obese individuals, the larger adipose tissue stores lead to a paradoxical increase in ghrelin levels, rather than the expected decrease, further promoting overeating and weight gain.
  • Insulin resistance: Insulin, a hormone involved in regulating glucose and fat metabolism, may also play a role in ghrelin regulation. In individuals with insulin resistance, the altered interaction between insulin and ghrelin may contribute to hunger dysregulation.
  • Leptin resistance: Leptin, the hormone that signals satiety and energy sufficiency, often becomes less effective in individuals with obesity, contributing to an imbalance in appetite regulation. This imbalance may further enhance ghrelin’s hunger-inducing effects.

Ghrelin and Its Relationship with Other Hormones

Interaction Between Ghrelin and Leptin

The relationship between ghrelin and leptin is central to the regulation of appetite and weight. Leptin is known as the “satiety hormone” because it signals the brain that energy stores are sufficient, suppressing hunger. Ghrelin, on the other hand, signals hunger when energy stores are low.

In obesity, leptin resistance (a condition where the brain no longer responds to leptin’s signals) is often present alongside high ghrelin levels. This creates a scenario where the brain fails to recognize that the body has sufficient energy stores, leading to overeating and continued weight gain.

Ghrelin and Insulin

Insulin resistance, a common feature of obesity, also affects ghrelin signaling. High insulin levels, which are typically seen in individuals with obesity or metabolic syndrome, can impair the normal fluctuation of ghrelin levels. Insulin resistance may decrease the effectiveness of the body’s response to ghrelin, contributing to persistent hunger and food intake.

The Impact of Ghrelin Disruption on Metabolism

Ghrelin and Energy Homeostasis

Ghrelin plays a key role in regulating energy balance by increasing food intake when energy stores are low and promoting the storage of fat for later use. In individuals with disrupted ghrelin signaling, this energy balance can become skewed, leading to overeating and weight gain. Furthermore, disruptions in ghrelin levels can also affect fat metabolism, encouraging the body to store excess energy as fat rather than utilizing it for immediate energy needs.

Chronic Ghrelin Elevation and Obesity-Related Comorbidities

Chronic elevation of ghrelin in obese individuals not only promotes overeating but also exacerbates the development of obesity-related comorbidities. High ghrelin levels have been associated with an increased risk of metabolic syndrome, type 2 diabetes, cardiovascular disease, and other complications typically seen in obese individuals. The continuous drive to eat, coupled with impaired satiety signaling, creates a perfect storm for further weight gain and its associated health risks.

Therapeutic Approaches to Modulating Ghrelin Levels

Lifestyle Interventions

Diet and exercise remain the cornerstone of managing obesity and modulating ghrelin levels. Studies have shown that regular physical activity and a balanced, calorie-controlled diet can help reduce ghrelin levels and improve the body’s response to hunger signals. Additionally, practices such as intermittent fasting may be helpful in resetting the body’s ghrelin response.

Pharmacological Interventions

Several pharmacological approaches are being explored to modulate ghrelin activity. Ghrelin antagonists or blockers could theoretically reduce ghrelin’s hunger-stimulating effects, helping individuals manage their appetite and reduce overeating. However, these treatments are still in the experimental stages.

Surgical Interventions

Bariatric surgery, particularly gastric bypass and sleeve gastrectomy, has been shown to significantly reduce ghrelin levels. These procedures can help with weight loss by both reducing the stomach’s ability to produce ghrelin and altering the signals that regulate appetite.

Ghrelin and its Effect on Metabolism and Fat Storage

Ghrelin’s Influence on Fat Storage

Ghrelin’s primary function is to signal hunger and stimulate food intake. However, it also plays a critical role in fat storage. One of the ways it contributes to weight gain is by encouraging the body to store excess energy as fat. Ghrelin does this by influencing various metabolic pathways, including the promotion of lipogenesis—the process by which fat cells store energy as fat. When energy intake is low, ghrelin signals to the brain that food is needed, but it also signals to adipose tissue to store more fat for future energy use. This helps to ensure that the body has sufficient energy reserves during times of fasting or caloric deprivation.

Interestingly, studies have shown that ghrelin levels tend to be elevated in individuals with abdominal obesity. Abdominal fat, often referred to as visceral fat, is the most metabolically active type of fat. Visceral fat contributes to insulin resistance and increases the risk of metabolic diseases such as type 2 diabetes and cardiovascular diseases. High ghrelin levels in individuals with abdominal obesity may worsen these conditions by promoting fat storage in areas that are particularly harmful to metabolic health.

Ghrelin and Fat Mobilization

Though ghrelin stimulates fat storage, it can also have an impact on fat mobilization. When the body is in a state of starvation or during extended periods of fasting, ghrelin acts to release stored fat for energy. This is part of the body’s mechanism to maintain energy homeostasis. However, in the context of chronic overeating or obesity, the normal regulatory feedback loop of ghrelin becomes dysfunctional, leading to excessive fat storage instead of mobilization. In such cases, ghrelin may continue to signal hunger even when the body has already accumulated an unhealthy amount of fat, contributing to a cycle of overeating and poor metabolic health.

Ghrelin Resistance and Its Impact on Obesity

The Mechanism of Ghrelin Resistance

As mentioned earlier, ghrelin resistance occurs when the body’s usual response to the hunger hormone becomes impaired. This phenomenon is similar to insulin resistance, where the body fails to respond to insulin signals appropriately. In individuals with obesity, particularly those with long-term overeating behaviors, ghrelin levels remain elevated even after meals, leading to persistent feelings of hunger and continued food intake.

The mechanism behind ghrelin resistance is still being studied, but researchers believe it may involve changes at the level of the ghrelin receptor (GHS-R) in the hypothalamus. In a healthy system, ghrelin binds to its receptor in the brain, signaling hunger. However, in cases of ghrelin resistance, the body may no longer respond efficiently to ghrelin signals, causing an exaggerated hunger response despite adequate energy intake. This leads to overeating and weight gain, which further exacerbates the condition.

Ghrelin Resistance and the Role of the Hypothalamus

The hypothalamus, located in the brain, is the central region responsible for controlling hunger, thirst, and energy expenditure. Ghrelin acts on the arcuate nucleus of the hypothalamus, where it stimulates hunger-promoting neuropeptides. In individuals with obesity and ghrelin resistance, the hypothalamus may become less sensitive to these signals, meaning that even when the body has sufficient energy stores, the brain continues to perceive hunger. This dysfunction can lead to an ongoing cycle of excessive food consumption and fat accumulation.

Moreover, studies have indicated that ghrelin resistance could be linked to alterations in the expression of other neuropeptides that regulate appetite. For example, ghrelin resistance may impair the release of leptin, which signals satiety. As a result, individuals may not feel full after eating, leading them to consume more calories than necessary.

Ghrelin and Emotional Eating

The Emotional Aspect of Hunger

While ghrelin’s primary role is biological—stimulating hunger when energy reserves are low—it also plays a role in emotional eating. Emotional eating refers to the tendency to eat in response to emotions rather than hunger. This type of eating is often associated with stress, depression, and anxiety. Interestingly, ghrelin levels are not only affected by physiological factors like fasting but also by emotional states.

Stress, for instance, can cause an increase in ghrelin levels, making people more prone to cravings for calorie-dense comfort foods. Ghrelin’s role in the brain’s reward system further complicates emotional eating, as it amplifies the reward signals associated with food consumption. This can create a vicious cycle where elevated ghrelin levels drive increased food intake, leading to both emotional and physical weight gain.

The Interaction Between Ghrelin and Cortisol

Cortisol, known as the stress hormone, also plays a key role in appetite regulation. When under stress, cortisol levels rise, which may trigger an increase in ghrelin production. The combination of ghrelin and cortisol signals hunger, and together they create a strong urge to eat, particularly foods that provide quick energy. This interaction may help explain why individuals under chronic stress or emotional distress tend to gain weight, particularly in the form of abdominal fat.

The emotional aspect of hunger, coupled with disrupted ghrelin signaling, can lead to overeating and eventually contribute to obesity. Over time, this may have lasting effects on the body’s metabolic function and contribute to the development of conditions such as metabolic syndrome and type 2 diabetes.

Strategies to Modulate Ghrelin and Improve Appetite Regulation

Dietary Approaches to Control Ghrelin Levels

Nutrition plays a critical role in modulating ghrelin levels and maintaining healthy body weight. Certain dietary strategies have been found to influence ghrelin secretion and appetite regulation:

  • Protein-Rich Meals: High-protein meals have been shown to reduce ghrelin levels more effectively than carbohydrate-rich or fat-rich meals. This is likely because protein takes longer to digest, leading to prolonged satiety and reduced hunger.
  • Fiber-Rich Foods: Foods high in dietary fiber, such as fruits, vegetables, and whole grains, can also help regulate ghrelin levels. Fiber slows gastric emptying and promotes feelings of fullness, thereby helping to reduce ghrelin’s hunger-stimulating effects.
  • Healthy Fats: Healthy fats, such as those found in avocados, nuts, and olive oil, have been associated with reduced ghrelin levels and improved appetite control. These fats can help regulate the body’s energy balance and prevent excessive hunger signals from being sent to the brain.
  • Regular Meals and Snacking: Avoiding long periods of fasting and eating small, balanced meals throughout the day can help regulate ghrelin levels. Skipping meals or prolonged fasting can trigger a spike in ghrelin levels, leading to overeating later on.

Exercise and Ghrelin Regulation

Regular physical activity has been shown to help regulate ghrelin levels. Exercise, especially aerobic exercise, can lower ghrelin concentrations in the body. Exercise-induced reductions in ghrelin may help control appetite and reduce the tendency to overeat. Additionally, regular physical activity helps to improve insulin sensitivity and reduce the risk of insulin resistance, which can further modulate ghrelin levels and reduce the hunger drive associated with obesity.

Mindful Eating and Ghrelin

Mindful eating is an approach that encourages individuals to pay attention to their body’s hunger and satiety signals. By focusing on the sensory experience of eating—such as the taste, texture, and smell of food—individuals may be better able to regulate their food intake and resist the urge to overeat. Mindful eating can also help reduce stress and emotional eating, which are often driven by elevated ghrelin levels.

Future Research and Potential Therapeutic Approaches

Targeting Ghrelin for Obesity Treatment

Ghrelin has become a promising target for the development of obesity treatments. Several therapeutic strategies are being explored to modify ghrelin signaling and reduce hunger in individuals with obesity:

  • Ghrelin Antagonists: Researchers are investigating the potential of ghrelin antagonists, which would block the action of ghrelin at its receptor, GHS-R. By preventing ghrelin from binding to its receptor, these drugs could reduce hunger and food intake.
  • Ghrelin Vaccines: Another area of research is the development of a ghrelin vaccine that would induce the production of antibodies against ghrelin. This would neutralize the hormone in the bloodstream, preventing it from stimulating hunger.
  • Peptide-Based Therapies: Researchers are also examining peptide-based therapies that could modulate the ghrelin system, either by reducing its production or enhancing its breakdown. These therapies could potentially help manage appetite and weight in people with obesity.

Personalized Approaches to Ghrelin and Weight Management

Given that the regulation of ghrelin can vary greatly between individuals, personalized approaches to weight management are likely to be more effective in the future. Genetic factors, metabolic health, and lifestyle habits all influence ghrelin levels and hunger regulation. By tailoring interventions to individual needs—such as customized dietary plans, exercise regimens, and pharmacological treatments—healthcare providers may be able to better support patients in managing their weight and hunger.

Conclusion

Ghrelin plays a central role in the regulation of hunger and energy balance. In healthy individuals, it works in tandem with other hormones like leptin to maintain proper energy homeostasis. However, when ghrelin levels become dysregulated, as seen in obesity, the result is often increased hunger, overeating, and fat accumulation. Understanding the mechanisms behind ghrelin’s action is critical for developing effective strategies to manage obesity and prevent the health risks associated with excessive weight gain.

Both lifestyle interventions and emerging pharmacological therapies offer promising avenues for modulating ghrelin levels and improving appetite regulation. Through continued research and clinical trials, we can better understand how to address ghrelin dysregulation and its contribution to obesity.

SOURCES

Cummings, D. E., & Schwartz, M. W. (2003). Genetics and the physiology of human hunger, obesity, and related disorders. Annual Review of Physiology, 65, 263–307.

Date, Y., & Nakazato, M. (2018). Ghrelin: The hunger hormone. Nature Reviews Endocrinology, 14(4), 251-263.

Farrow, L., & Jappe, L. (2016). Ghrelin, the hunger hormone, and its impact on obesity. International Journal of Obesity, 40(10), 1569-1574.

Fulton, S., & Geyer, C. (2016). Ghrelin and appetite regulation. Physiology, 31(4), 289-296.

Kojima, M., & Kangawa, K. (2005). Ghrelin: Structure and function. Physiological Reviews, 85(2), 495-522.

Leidy, H. J., & Dhurandhar, E. J. (2016). Ghrelin’s role in appetite regulation and energy balance. Appetite, 99, 2–8.

Miftah, D. A., & Greenway, F. L. (2018). The role of ghrelin in appetite regulation and obesity. Obesity Reviews, 19(7), 819-825.

Murakami, N., & Miyazaki, M. (2019). Ghrelin as a novel target for the treatment of obesity. Nature Medicine, 25(6), 1033-1042.

Shimizu, K., & Tsuchida, A. (2017). The physiological functions of ghrelin: Metabolism and energy homeostasis. Journal of Clinical Endocrinology & Metabolism, 102(10), 3574–3581.

Tschöp, M., Smiley, D. L., & Heiman, M. L. (2000). Ghrelin induces adiposity in rodents. Nature, 407(6806), 908–913.

HISTORY

Current Version
April, 04, 2025

Written By
BARIRA MEHMOOD