Ghrelin, is a recently discovered hormone, that stimulates feeding in humans has come under scrutiny as of late as a possible regulator of food intake and energy balance. This review will attempt to highlight some of the major research findings about ghrelin and assist the nutritional professional to decipher future research as it unfolds.

Background

First discovered in 1999 by Kojima and associates (Kojima et. al. 1999), ghrelin is a peptide hormone secreted by the empty stomach and consists of 28 amino acids. The name ghrelin, is derived the Indo-European root word ("ghre") meaning "growth" (Altman, 2002). An alternate name for ghrelin is "motilin-related peptide" coined by French scientists who independently isolated the hormone in the mouse and named it in light of its structural similarly to the duodenal hormone motilin (Wang et. al., 2002). Ghrelin is the first peptide isolated from natural sources in which the hydroxyl group of one of its serine residues is acylated by n-octanoic acid, an event that is critical for ghrelin's attachment to its receptor (Muccioli et. al. 2002). Non-acylated ghrelin also circulates (in greater abundance than the acylated form) in the body and appears to have other biological functions such as cardiovascular and possible anti-cell proliferation effects, properties which are still being investigated (Muccioli et. al. 2002).

Ghrelin and Growth Hormone Secretion

For years it has been commonly assumed that growth hormone (GH) secretion from the anterior pituitary results from the interaction of growth hormone releasing hormone (GHRH), which stimulates GH release and somatostatin, which inhibits it (Ukkola & Poykko, 2002). Prior to ghrelin's discovery, it was known for sometime that artificially created molecules called growth hormone secretagogues (GHSs) stimulated the release of GH via binding to a receptor which had no known ligand. It was experiments such as these that lead researchers to speculate that some heretofore unknown hormone must be present since a receptor for it was known to exist. Finally, in 1999 ghrelin was discovered (Kojima et. al. 1999). Ghrelin stimulates the release of GH when administered orally, intravenously, subcutaneously and transdermally (Ukkola & Poykko, 2002). Secreted from the stomach, ghrelin circulates in the blood and interacts with the hypothalamus to stimulate GH release. In both the human and rat brain, the greatest receptor density for ghrelin found to date is lies in the hypothalamus, pituitary and hippocampus (Wang et. al. 2002). Some evidence suggests that when ghrelin is administered to humans in conjunction with GHRH, that the combination elevates GH more than GHRH alone (Peino et. al. 2000), an effect that seems to be due to ghrelin's interaction with a separate population of pituitary cells than GHRH affects (Wang et. al. 2002). Peino and associates (2000) intravenously administered various dosages (.25 ug/kg - 6.6ug/kg) of ghrelin to twelve normal healthy males, 21-35 years of age. They observed a clear dose-dependant elevation in GH from ghrelin treatment with the greatest GH increase resulting from the highest amount of ghrelin administered. Interestingly, no increase in appetite was observed during any of the ghrelin dosages.

Ghrelin and Food Intake

Several investigators have found that ghrelin stimulates food intake, making it a possible major player in weight gain and obesity (Tschop et. al. 2000; Wren et. al. 2000). In humans, ghrelin levels are reduced in obese and overfed individuals (Muccioli et. al. 2002). Plasma ghrelin concentrations increase during fasting and dieting as well as in patients with anorexia nervosa (Hansen et. al., 2002; Muccioli et. al. 2002). Ghrelin levels also elevate before eating, an event which suggests that ghrelin may play a role in the signal that initiates eating.

Given that ghrelin stimulates GH release, a logical assumption would be to conclude that ghrelin may lead to weight gain via increase in muscle tissue. Ironically, this does not seem to be the case. Tschop and associates (2000) found that in rats, daily ghrelin treatment caused weight gain via the addition of fat mass accompanied by a reduction of fat as a fuel source. When continued, daily ghrelin treatment resulted in a dose-dependant increase in food intake and body weight gain, a finding that has been confirmed by other researchers (Wren et. al. 2000). Shintani and associates (2001) have observed that ghrelin is able to override leptin's inhibition of food intake, an event which may at least be partially responsible for ghrelin's observed increase in fat mass. Some evidence suggests that ghrelin levels decrease following gastric bypass surgery, which may further assist with weight loss following this procedure (Cummings et. al. 2002). Lastly, in a further demonstration of ghrelin positive role in energy balance, Nakazato and associates (2001) have found reduced food intake in rats following injection of ghrelin antiserum. It should be stated however that currently the role of ghrelin on energy balance in humans is unknown (Ukkola et. al. 2002). The increase in food intake, at least in rodents, following ghrelin infusion, occurs rapidly- less than 60 minutes (Wren et. al. 2000). Changes in body weight also occur fairly rapidly (within 48 hours) following ghrelin administration (Tschop et. al. 2000). In addition, an increase in the reparatory quotient in rodents following ghrelin administration, has also been observed, indicating a shift away from fat utilization and toward greater use of carbohydrate as a fuel source (Tschop et. al. 2000). This may also help explain ghrelin's impact on fat mass gain.

Other Sites of Ghrelin Synthesis

While the empty stomach is traditionally associated with ghrelin release, studies also reveal that ghrelin is produced in other areas of the body as well. For example, studies indicate that ghrelin is also produced in the pancreas, kidney, liver, hypothalamus and in various immune cells (Wang et. al. 2002). The role of ghrelin in these other areas is currently poorly understood. Additionally, the human placenta has also been observed to manufacture ghrelin particularly during the first trimester (Wang et. al. 2002). In the cardiovascular system, ghrelin (non-acylated version) appears to augment cardiac output in healthy humans via enhancing heart contractility (Nagaya et. al. 2001). Ghrelin has also been found in some forms of cancer (Nagaya et. al. 2001), leading some to speculate of possible future therapeutic applications (Penalva et. al., 2001).

Side Effects

Thus far, no studies have reported major side effects from ghrelin use in humans other than increased hunger sensations, an effect reported in 80% of subjects to date (Muccioli et. al. 2002). Ghrelin does not seem to alter blood pressure or heart rate in humans (Peino et. al. 2000). One investigation (Peino et. al. 2000) did report excessive perspiration in 2 subjects (N=6 in the study) who were exposed to higher levels of ghrelin (6.6 µg/kg). However, before a definitive answer can be made on safety, more research is warranted on side effects of pharmacologic treatments of ghrelin in humans.

Marketing Tactics

Given the widespread appeal of something that stimulates growth hormone and evidence that ghrelin antagonists seem to decrease feeding in rats, as well as evidence that ghrelin may enhance cardiac output in humans, it is not surprising that advertisements for ghrelin-related products are starting to appear in popular fitness magazines. This author has observed at least one product which purports to block the action of ghrelin, which the ad indicates, will lead to weight loss (Muscle & Fitness Hers, November 2002). It should be noted however that currently no peer reviewed evidence seems to have been conducted showing the effectiveness of ghrelin-blocking agents on weight loss in humans. Since some reports indicate that ghrelin seems to augment cardiac output, nutrition professionals should also be aware of possible ads for dietary supplements touting this ability to endurance athletes. Currently no exercise studies of ghrelin seem to have been conducted on humans. Lastly, registered dieticians and fitness professionals should take note of the oral effect of GH secretagogues when dealing with bodybuilders and other fitness-minded individuals, who are forever looking for ways to maximize muscular size and strength. It is the opinion of this author that GH secretagogues will be one of the next rages in the bodybuilding community. The lack of exercise studies on humans coupled with the lack of quality control among dietary supplements in general, makes these products a poor choice for consumers.

Unresolved Questions

In spite of the abundance of studies that have been conducted on ghrelin and GH secretagogues in the last few years several questions remain to be elucidated (Mucciloi et. al. 2002):
1. Studies have provided evidence that different types or subtypes of ghrelin receptors exist. Each type or subtype may have distinct effects. This leaves open to speculation that it may be possible one day to stimulate only one type of receptor, engendering only a specific type of response. This may have far reaching biomedical implications.
2. Further researcher is needed to better understand the time course of the observed alterations in body mass and body composition following both normal and pharmacologic dosages of ghrelin.
3. Most research to date on ghrelin has been conducted on rodents. While rodent ghrelin is almost identical to human ghrelin (Wang et. al. 2002), small variations in amino acid sequencing may lead to profoundly different biological effects between species especially when coupled with the finding that various types and subtypes of ghrelin receptors that have been found.
Since discovered in 1999, an abundance of research has been conducted on ghrelin showing that is both a potent stimulator of growth hormone release, and hunger in humans and rodents. This may require the re-writing of medical and biological textbooks since it appears that ghrelin is a third metabolic pathway for growth hormone regulation. Studies of ghrelin receptors indicate that several distinct types and subtypes exist which may have far reaching biomedical implications.