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Ghrelin: the Good & Bad + How to Increase/ Decrease Levels

Written by Puya Yazdi, MD | Last updated:
Medically reviewed by
Genius Labs Science Team | Written by Puya Yazdi, MD | Last updated:

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Stomach

Known as the hunger hormone, ghrelin stimulates appetite and promotes eating. It isn’t necessarily “good” or “bad,” though it may become dysregulated in various health conditions and disease states. When is ghrelin beneficial, and when can it do harm? Learn more here.

What is Ghrelin?

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Ghrelin is a hunger hormone that stimulates appetite and is mainly produced by specialized stomach cells [1, 2].

Ghrelin is considered a multi-functional hormone that is also produced by various tissues and organs including the gut, pancreas, kidney, reproductive organs, placenta, bone, and brain [3, 4, 5].

Regulation

Injections of ghrelin in both humans and mice have been shown to increase food intake in a dose-dependent manner: the more ghrelin someone has in their bloodstream, the more they eat [6, 7].

The less body fat we carry, the more ghrelin we produce: a mechanism by which the body maintains body weight and promote increased food intake if it doesn’t have sufficient fat reserves [8].

Ghrelin gets released into the blood and goes into the brain, where it sends a hunger signal to the hypothalamus. Ghrelin receptors are found in high concentrations in the hypothalamus of the brain and in the pituitary gland [9, 10].

Effects

Ghrelin sends a signal that we don’t have enough energy, that we need to eat, and that we need to conserve our energy [11].

Chronically elevated levels of ghrelin are associated with obesity, overeating, and inflammation-related diseases including ulcerative colitis, Crohn’s disease, pancreatitis, and possibly rheumatoid arthritis [12].

Ghrelin affects the immune system, the reproductive system, strengthens the bones, and promotes muscle development [12].

Beneficial Roles in Health

This section is a discussion of the role of ghrelin in general health. None of these should be taken as a reason to try to increase ghrelin levels artificially; if the ghrelin system is dysregulated, an underlying health condition is likely at fault.

If you feel that you are unusually hungry, if you have runaway weight gain, or if you are suffering from another symptom that you believe could be connected to ghrelin, talk to your doctor about the possible causes and appropriate treatment or management plans available to you.

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1) Regulating Inflammation

A number of reports describe ghrelin to be a potent anti-inflammatory mediator both in organisms and in cells and a promising therapeutic agent for the treatment of inflammatory diseases and injury.

Ghrelin inhibits NF-kB and reduces the production of inflammatory cytokines, such as TNF-α, IFN-γ, IL-6, IL-1α, IL-1β, IL-12, IL-18, IL-17, IL-15 [13, 12].

Ghrelin is needed for immune tolerance. It increases the anti-inflammatory cytokine IL-10 [12].

Ghrelin suppresses Th1-type immune responses and promotes the Th2-type immune response [14].

Indeed, ghrelin exerts anti-inflammatory actions in Inflammatory Bowel Disease (IBD), pancreatitis, sepsis, arthritis, and diabetic nephropathy [15, 16].

Ghrelin reduces cell death and increases cell production [12].

Ghrelin protects cells against toxic by-products of oxygen reactions and inflammatory injury [12], which is signaled by pain, heat, redness, swelling, and loss of function [17].

Elderly patients aged 70 and older, who cannot produce as much ghrelin as younger patients, experience more severe inflammatory disease symptoms [17].

2) Autoimmune Disease

Ghrelin may help patients with autoimmune/inflammatory diseases, including rheumatoid arthritis, ulcerative colitis, multiple sclerosis, Parkinson’s disease, Crohn’s disease, cardiovascular disease, and inflammation from brain injury [12].

Ghrelin protects the lungs, liver, kidneys, and other organs from toxic by-products of oxygen reactions and inflammation injury [12].

Ghrelin has shown potent anti-inflammatory effects in rat and mice models of arthritis, resulting in a slowed progression of the disease [12].

Ghrelin also protects the heart from inflammation injury and improves heart function in mouse models of heart disease [12].

3) Learning and Memory

Ghrelin produced in the stomach can enter the hippocampus (an area of the brain important for long-term memory storage) through the blood.

In mouse brains, ghrelin alters the connections between nerves and cells to enhance learning and memory [18, 19].

Similarly, rats injected with ghrelin demonstrated better memory retention [20].

Restricting calorie intake, which has been shown to increase ghrelin levels, improved memory in elderly people [21].

Ghrelin receptors are more concentrated in the hippocampus [19] and ghrelin likely increases hippocampal neurogenesis [22].

Ghrelin increases CREB and BDNF production [23].

Ghrelin may enhance neuronal firing by activating the NMDA receptor [19].

Blocking the ghrelin receptor type 1a (GHSR1a) impairs both memory acquisition and memory consolidation in rats [24].

Ghrelin is neuroprotective [25] and activation of the Growth Hormone/IGF-I axis (by ghrelin) is a potential Alzheimer’s treatment [26] and Parkinson’s treatment [27].

4) Stomach Acid and Gut Flow

When supplemented, Ghrelin dose-dependently increases stomach acid secretion [28, 29], by a mechanism involving the vagus nerve [30, 29] and histamine synthesis and release [31].

In cells, ghrelin dose-dependently enhances the contraction of stomach muscle cells when stimulated [32].

Several studies have shown a dose-dependent effect of ghrelin on quickening stomach emptying and intestinal transit in rodents. The vagus nerve in part mediates this effect [33].

Ghrelin has been shown to have a series of important therapeutic potentials for the treatment of gut motility disorders, such as constipation [33].

5) Heart Disease

Ghrelin decreases blood pressure in healthy subjects [34].

In animal models with heart failure, ghrelin improved cardiac output [35].

In patients with chronic heart failure, ghrelin improved heart function, increased heart output and increased muscle strength [36].

The mechanisms responsible for the low blood pressure effects of ghrelin include the suppression of fight or flight activity [37], inhibiting the renin-angiotensin system in humans [38] or direct vasodilatory action [39, 40].

Acute ghrelin treatment improved survival in a heart attack by preventing an increase in the frequency of heart arrhythmias (rats) [41].

6) Bone Formation

Bone formation is induced by ghrelin. Ghrelin stimulates bone promoting cells (osteoblasts) and increases bone mineral density, by an unknown mechanism [42, 43].

In humans, blood ghrelin level was positively correlated with bone mineral density in peri-, post-, and premenopausal women [44].

In a randomized, double-blind, placebo-controlled study, ghrelin infusion had no acute effect on markers of bone turnover in healthy controls. However, people who had high ghrelin levels had less bone destruction [45].

7) Growth Hormone

Ghrelin causes the release of growth hormone by activating the growth hormone secretagogue receptor [46].

The growth hormone secretagogue receptor (GHSR) increases growth hormone release [47].

Many of the benefits of ghrelin come as a result of activating this receptor.

8) Mitochondria

Ghrelin increases the production of mitochondria [25].

Ghrelin is a robust activator of mitochondrial function in the hypothalamus [25].

Ghrelin reduces free radicals by increasing UCP2 in the brain [25].

Ghrelin has been shown to stimulate AMPK and SIRT1 [33].

9) Dopamine

In animals, Ghrelin enhanced dopamine release in the hypothalamus [47], amygdala [48], and nucleus accumbens (pleasure center) [49] (via GHSR).

Ghrelin also amplifies dopamine action (via GHSR) [50].

This dopamine release and amplification can increase physical activity [49] and motivation.

Indeed, Ghrelin and its receptor (GHSR) prevents depressive-like behavior [22, 25].

Possible Detrimental Roles in Health

This section is a discussion of the role of ghrelin in general health. None of these should be taken as a reason to try to decrease ghrelin levels artificially; if the ghrelin system is dysregulated, an underlying health condition is likely at fault.

If you feel that you are suffering from symptoms that you believe could be connected to ghrelin, talk to your doctor about the possible causes and appropriate treatment or management plans available to you.

1) Anxiety

Whether ghrelin acts as an antidepressant or as a depressant is debated.

Recent studies suggest that Ghrelin may have antidepressant properties.

Antidepressant-like behaviors in mice have been observed in response to increased ghrelin levels. These mice were more social and motivated to survive in a forced swim test [51].

However, a study on rats found that ghrelin activity in the brain caused depressive-like behaviors. These rats were less motivated to survive in a forced swim test [52].

Most studies, however, agree that ghrelin is associated with anxiety.

Mice injected with ghrelin had higher levels of the stress hormone cortisol and demonstrated anxiety-like behaviors.

Similar results were found in rats with increased ghrelin levels. These rats were less social and avoided open areas [52].

2) Weight Gain and Obesity

Ghrelin acts as a signal to the brain to induce food intake [53] and enables the storage of surplus calories in fat cells [54].

People who are trying to lose weight or fasting may produce more ghrelin [55].

The more fat you have, the less ghrelin you produce, which is supposed to make you thinner and keep your weight in homeostasis [8].

Ghrelin favors the accumulation of stomach fat [56], which in turn favors the formation of liver fat and increases the risk of developing insulin resistance [57].

Chronically high levels of ghrelin have been shown to increase food intake and promote fat storage in white and brown fat cells [58].

Chronically high levels of ghrelin promote fat storage and weight gain in mouse models [59].

In healthy individuals, ghrelin is secreted when the stomach is empty, letting you know when it’s time to eat [6].

Ghrelin has been shown to increase consumption of, and preference for, high-fat foods in mice [59], rats [7], monkeys [60], and in people [59].

In healthy individuals, ghrelin levels fall after eating to reduce appetite and food intake [6].

However, in obese subjects, ghrelin levels do not significantly decrease after a meal [61].

Obese children regain fasting levels of ghrelin more rapidly than healthy children [11].

This suggests that for obese and overweight people, ghrelin causes a biased pattern of increased food consumption, decreased energy expenditure, and increased fat storage and weight gain.

Obese and overweight individuals tend to have lower ghrelin levels than healthy individuals, suggesting that ghrelin does not directly contribute to obesity except in patients with Prader-Willi Syndrome whose exceptionally high levels of ghrelin are correlated with obesity and over-eating [62, 63].

In the liver and fat tissue, ghrelin inhibits AMPK activity [64] and increases PPAR gamma, lipoprotein lipase, and perilipin [65, 66].

4) Anorexia Nervosa

High ghrelin levels are associated with conditions characterized by a lack of energy, resulting in weakness and wasting of the body. Such conditions include anorexia, cancer, chronic disease, and chronic failure of the heart, kidneys, and lungs [67].

When individuals with anorexia nervosa fast, they have higher fasting levels of ghrelin than in healthy individuals. These increased ghrelin levels may be an adaptive response to stimulate eating [68].

According to some researchers, increased ghrelin levels may indicate the development of ghrelin resistance; that is, the body may be producing normal amounts of ghrelin, but it doesn’t stimulate the appetite. This has been demonstrated in animal models: in mice suffering from cancer-related wasting, ghrelin’s ability to stimulate appetite was reduced [69].

Ghrelin treatments have been shown to increase caloric intake in cancer patients with impaired appetite [70] and in healthy volunteers [6].

Ghrelin has been found to counteract muscle and tissue wasting syndromes associated with cancer, heart disease, and chronic disease [12].

5) Fertility

Ghrelin has been found to inhibit the function and reproduction of sex cells in male and female animals. In male animals, high ghrelin levels inhibit sperm production [71].

In the female reproductive system, high ghrelin levels prevent changes in the uterus that are necessary for fertilization [72].

Ghrelin inhibits gonadotropin-releasing hormone (GnRH), LH, FSH [73] and progesterone secretion [74], and stimulates of prolactin [75].

Ghrelin also inhibits hCG and testosterone release by testicular cells [76, 77].

This is one mechanism by which calorie restriction may inhibit fertility:

Calorie restriction->higher ghrelin ->lower testosterone and progesterone.

6) Cancer

Whether ghrelin contributes to or inhibits the growth and proliferation of cancers is hotly debated. However, most cell studies have found that ghrelin contributes to cancerous growths by promoting cell production and preventing cell death [78].

Ghrelin may promote the ability of cancer cells to migrate to and invade other parts of the body (to metastasize) [79].

This spread and growth make cancers difficult to treat, resulting in lower life-expectancy [79].

In a laboratory study of cancer, blocking ghrelin production in cells reduced the spread of cancer [79].

7) Risk-Taking Behavior

Risk-taking behavior has been observed in hungry animals that take more risks searching for food when they are running low on energy [80, 81].

Similarly, in humans, fasting-induced ghrelin levels caused people to make riskier economic choices. Normal risk avoidance was restored immediately after eating. The authors suggested that higher ghrelin levels may cause us to make bad decisions [82].

8) Stress Response

Ghrelin activates the HPA axis and causes a release of cortisol [22, 83].

Genetics

GHRL Gene (Produces Ghrelin):

  1. RS34911341 (GHRL)
  2. RS35683 (GHRL)
  3. RS42451 (GHRL)
  4. RS4684677 (GHRL)
  5. RS696217 (GHRL)

GHSR Gene (Ghrelin Receptor):

  1. RS2232165 (GHSR) GG
  2. RS2922126 (GHSR) AA
  3. RS2948694 (GHSR) GG
  4. RS490683 (GHSR) GG
  5. RS572169 (GHSR) CC
  6. RS9819506 (GHSR) TT

Testing Ghrelin

Ghrelin levels change throughout the day. They are higher at night and lower during the day [63].

During the day, ghrelin is highest during a fasting period when the stomach is empty, and lowest right after a meal [55].

Doctors won’t often order a ghrelin test; there are better and more reliable alternatives for any conditions that might be indicated by high or low ghrelin.

The “Ghrelin Test” in GH Deficiency

Challenging with ghrelin may help identify growth hormone (GH) deficiency, in particular after aneurysmal subarachnoid hemorrhage. In this test, the patient is given ghrelin intravenously, and their growth hormone levels are monitored thereafter. Because ghrelin strongly provokes GH release, the patient’s response indicates whether or not they have GH deficiency [84].

Factors that Increase Ghrelin

Some factors have been associated with increased ghrelin production or release in humans. Increasing (or decreasing) ghrelin may or may not be beneficial to one’s health; your doctor can help you decide what strategies are best for your health. Talk to your doctor before making significant changes to your diet, lifestyle, or supplement regimen.

  • Fasting: ghrelin is secreted when the stomach is empty [55].
  • Fiber: in one study, people who regularly eat more fiber in their diets produced more ghrelin under fasting conditions [85].
  • Resistant starch: in a small study of 10 patients, resistant starch intake increased fasting ghrelin levels [86].
  • Zinc: zinc levels in the hair (an indicator of long-term zinc intake) were associated with ghrelin levels in the blood in children [87].

Lifestyle Factors

  • Weight loss: ghrelin production decreases as fat mass increases [55, 88].
  • Sleep deprivation: even one night of sleep deprivation led to increased ghrelin levels in healthy volunteers. We do not recommend deliberately depriving yourself of sleep for any reason [89].
  • Chronic stress increases ghrelin and appetite [90].

Factors that Reduce Ghrelin

Likewise, some factors have been associated with decreased ghrelin production or release in humans. Decreasing ghrelin may or may not be beneficial to one’s health; your doctor can help you decide what strategies are best for your health. Talk to your doctor before making significant changes to your diet, lifestyle, or supplement regimen.

  • High protein meals [91, 92]: ghrelin levels after eating a high-protein meal were much lower compared to ghrelin levels after a high-calorie meal.
  • Adequate sleep [89]
  • Ketogenic diet [93]
  • Acupuncture [94]
  • Vitamin D status: ghrelin was higher in people who were deficient in vitamin D3. This does not necessarily mean that more vitamin D will reduce ghrelin in people who aren’t deficient [95].
  • Honey: when used in place of sugar, honey delayed the ghrelin response in a small study of 14 healthy women [96].

Irregular Ghrelin Levels?

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About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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