Redrawn from images by Masayasu Kojima
Obesity is big. A public with a seemingly insatiable appetite for weight-loss products spends more than $35 billion (US) annually on diet products or programs in North America, according to the US Federal Trade Commission. And, basic research findings are accumulating like calories at the holidays. "Recent years have witnessed explosive growth in knowledge of the physiological factors regulating appetite and body weight," stated an editorial last year.1
The first three of this issue's Hot Papers2-4, all from Japanese teams, bolster the idea that ghrelin, a peptide originally implicated in the release of growth hormone, plays a central role in appetite regulation in rodents. A fourth paper from a group at Eli Lilly and Co. shows that, in humans, ghrelin's involvement in the process is less straightforward than expected.5 These findings have important implications for manipulating ghrelin physiology in the quest for drugs to counter eating disorders such as obesity and anorexia.
THE HUNGER HORMONE Kenji Kangawa and Masayasu Kojima of Japan's National Cardiovascular Center Research Institute in Osaka discovered ghrelin in 1999.6 About 20 years earlier, Cyril Bowers from Tulane University, New Orleans, had started a line of inquiry, described as reverse pharmacology, whereby the receptors for synthetic growth hormone secretagogues in the pituitary and hypothalamus were identified prior to their endogenous ligand. That ligand, ghrelin, was found to be synthesized by X/A-like cells in the stomach, a strange site for the source of a molecule that stimulates growth hormone secretion.
Soon afterwards, the Lilly team discovered that an infusion of ghrelin stimulates feeding and obesity in rodents.7 "That created huge excitement," says long-time obesity researcher Jeffrey Flier, chief academic officer at Beth Israel Deaconess Medical Center in Boston. "The next wave of papers that began to explore the potential role of ghrelin in body weight regulation ... got a huge amount of attention."
The ensuing flurry of research reinforced the putative role for ghrelin in energy balance. Miyazaki Medical College scientists, led by Masamitsu Nakazato, showed that neutralizing natural endogenous ghrelin by central administration of a ghrelin antibody decreases food intake in rats.2 That's a major finding, says former Lilly team member Matthias Tschöp, who now researches obesity at the University of Cincinnati, "because it suggests that if you have a drug against ghrelin, you might reduce appetite."
Furthermore, the antibody treatment was associated with activity of the neuronal activation marker, Fos protein, producing neuropeptide Y (NPY) and agouti-related protein. Such proteins are known to be downregulated by the appetite-suppressing hormone leptin, suggesting it is the yin to ghrelin's yang. A month later, Yoshiro Ogawa and colleagues at the Kyoto University Graduate School of Medicine published their paper showing that administration of an NPY-Y1 antagonist completely reverses ghrelin-induced increases in food intake.3
Kojima, a coauthor on both papers, and now professor of molecular genetics at Japan's Karume University, says these studies were "the first to show the effects of ghrelin on neuropeptide Y in the arcuate nucleus." This region of the hypothalamus is known to be involved in energy balance. At about the same time, Kobe University researchers implicated the gastric vagal nerve by showing that ghrelin's effect on appetite through NPY was lost after vagotomy in rats.4 NPY's importance in mediating ghrelin's effects remains "unresolved," says Flier, in light of more recent findings that these effects persist in NPY knockout mice.
A BIG, FAT DISAPPOINTMENT Ghrelin administration increases appetite and adiposity in rodents, but the connection to human obesity has been harder to come by. Under the leadership of Lilly's Mark Heiman, Tschöp compared circulating ghrelin levels in obese and lean subjects, including a cohort of Pima Indians, a population with a particularly high rate of obesity.5 This was, says Tschöp, "the first paper to show something about the role of ghrelin in humans."
Surprisingly, the findings revealed a negative correlation between circulating ghrelin levels and obesity. "If you are looking for a good target to fight obesity, that paper meant a disappointment," says Tschöp. "Why would you decrease ghrelin levels if they are already low?" Tschöp says that the result does not, however, completely discount ghrelin as an anti-obesity target. "It is still the only peripherally circulating hormone that increases appetite and body weight," he says. "A ghrelin receptor antagonist might neutralize the crucial remaining ghrelin obese patients have and decrease body weight."
But there are other reasons for caution, Kojima points out. Because ghrelin has been implicated in numerous processes, such as the regulation of cardiovascular function and stress responses, and growth hormone secretion, blocking ghrelin may cause unpredictable adverse effects: "Complete lack of ghrelin may be harmful," says Kojima, "but suppression of ghrelin may be effective for obesity without side effects."
BOUNCING BACK This is a familiar story. Researchers hoped that the appetite-reducing hormone leptin, discovered in 1994, would become an anti-obesity drug. The hope was scuppered when high leptin levels were found in overweight subjects.
Optimism, however, remains for ghrelin. David Cummings, associate professor of medicine at the University of Washington, showed that circulating ghrelin levels rise before meals and fall rapidly afterwards in humans,8 suggesting a short-term, meal-to-meal appetite regulatory role for ghrelin. Tschöp suggests that control in the short term may affect long-term energy balance.
Cummings also found that, though diet-induced weight loss leads to an increase in ghrelin levels and, therefore, appetite, this is not the case for severely obese patients who have undergone gastric bypass surgery. This finding could explain the greater long-term success of the surgical procedure compared to dieting. And, if surgery somehow prevents the stomach from communicating with the brain through ghrelin, then ghrelin receptor antagonists could help to avoid weight gain once it is lost. "That remains a very active area for ... discussion and speculation," says Flier.
As for other avenues, both Kojima and Tschöp are intrigued by a ghrelin characteristic that is unique among mammalian hormones: an octanoyl fatty acid side chain found in some forms. Ninety percent of circulating ghrelin lacks the side chain, leading Tschöp to speculate that ghrelin reaches the brain in an inactive state. "In collaboration with Professor Bill Banks from St. Louis, we found ... that in a mouse model, ghrelin with the side chain could not cross from the periphery to the brain barrier, at least not easily."
Perhaps the two forms of ghrelin have different functions. "There is some intriguing evidence that nonacylated ghrelin is inactive in the regulation of growth hormone release and energy balance regulation, but is active in cardiovascular effects and cell proliferation control," says Tschöp. Antagonists of the mystery enzyme that catalyzes this octanoyl modification, says Kojima, may be another target for ghrelin-suppressive drugs.
Researchers, including Tschöp's group, seek the elusive ghrelin receptor antagon-ists and are testing several candidates. Success will permit investigation into endogenous ghrelin's effects on energy balance. The evidence accumulated so far is largely circumstantial: Endogenous system studies are descriptive, says Tschöp, while the effects of ghrelin-administration experiments could be purely pharmacological. "It will be very interesting to see," says Tschöp, "if the whole theory [that] ghrelin ... regulates energy balance via the brain--the so-called hunger hormone--will just collapse, or be confirmed by ghrelin receptor antagonist studies."
Stuart Blackman (email@example.com) is a freelance writer in Edinburgh, UK.
1. J.S. Flier, E. Maratos-Flier, "The stomach speaks--ghrelin and weight regulation," N Engl J Med, 346:1662-3, 2002.
2. M. Nakazato et al., "A role for ghrelin in the central regulation of feeding," Nature, 409:194-8, 2001. (Cited in 203 papers)
3. M. Shintani et al., "Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway," Diabetes, 50:227-32, 2001. (Cited in 103 papers)
4. A. Asakawa et al., "Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin," Gastroenterology, 120:337-45, 2001. (Cited in 115 papers)
5. M. Tschöp et al., "Circulating ghrelin levels are decreased in human obesity," Diabetes, 50:707-9, 2001. (Cited in 117 papers)
6. M. Kojima et al., "Ghrelin is a growth-hormone-releasing acylated peptide from stomach," Nature, 402:656-60, 1999.
7. M. Tschöp et al., "Ghrelin induced adiposity in rodents," Nature, 407:908-13, 2000.
8. D.E. Cummings et al., "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery," N Engl J Med, 346:1623-30, 2002.