Endocrinology

For more than a decade, researchers have been investigating two hormones that may provide endocrinologists and nutritionists with a new tool to identify patients in need of specialized weight-loss programs that target appetite hormone levels.

“Ghrelin and leptin [research studies] are emblematic of our increasing understanding of appetite in humans. We have learned so much about the regulation of energy balance since the ’90s, and these two hormones represent some of the progress made,” said

W. Timothy Garvey, MD, of the department of nutrition sciences at the University of Alabama at Birmingham; Geriatric Research, Education and Clinical Center investigator and staff physician at Birmingham VA Medical Center; and director of the UAB Diabetes Research and Training Center.

W. Timothy Garvey, MD, said recent discoveries in the regulation of energy balance identify new potential therapeutic targets for the obesity epidemic.

Source: W. Timothy Garvey, MD, reprinted with permission.

“These discoveries identify new potential therapeutic targets for treating the obesity epidemic. Hopefully, in a few years time, we will have more information regarding rational approaches on how to prevent obesity, and prevent and treat diabetes based on this biomedical progress,” Garvey told Endocrine Today.

Much has been learned, for example, about leptin’s potential use to treat lipodystrophy and ghrelin’s role in appetite regulation, and additional research is on the horizon.

Additionally, a number of other disorders beyond obesity are affected by or characterize these hormones’ role, such as cachexia related to cancer, chronic renal insufficiency, restrictive eating disorders and Prader-Willi syndrome. Endocrine Today spoke with several experts in the field about these hormones.

Initial discovery, hormones’ roles

Leptin is a fat cell hormone that plays a key role in metabolism regulation and was first discovered in 1994.

“The discovery of leptin was significant in that it was a major breakthrough and one of the first significant hormones identified that was implicated in weight regulation,” said Jennifer B. Hillman, MD, assistant professor of pediatrics in the division of adolescent medicine at the Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, College of Medicine.

This discovery, she said, stimulated a new area of research and led to the study of regulating energy intake and expenditure, including appetite and metabolism and weight-related disorders.

To date, Hillman said more than 30,000 articles have been published on leptin.

Early on, there was hope that the discovery of these hormones would result in a cure for obesity. However, Hillman said it soon became clear that defects of leptin and its receptor are rare, and the effect on common forms of obesity would be minimal.

“That being said, the discovery of leptin is still a significant scientific breakthrough in the understanding of obesity. The benefits and impacts are still being seen as researchers continue to understand all the ways in which leptin works,” she said.

Elif A. Oral, MD, associate professor of medicine and medical director of bariatric surgery at the University of Michigan, division of metabolism, endocrinology and diabetes, said the discovery of leptin completely changed the understanding of obesity.

Elif A. Oral

“While it did not prove to be the magic bullet drug for obesity, the revolution it created in the fundamentals of energy balance is paramount,” Oral told Endocrine Today. “In this framework, where we begin to view the regulation of food intake as a biological drive as opposed to a sign of weak will, the signals coming out of the gastrointestinal tract are also important.”

And so the discovery of ghrelin — a 28 amino acid peptide and a hormone produced by cells in the stomach and pancreas — in 1999 was equally exciting, according to Hillman. Ghrelin has also been shown to stimulate growth hormone.

“It was the first known substance to stimulate food intake,” she said. “It is a powerful hormone, and the implications of ghrelin and ghrelin-related proteins are yet to be seen.”

With its discovery came the understanding of another means by which the human body regulates weight. Specifically, ghrelin levels are lower in those who are obese, therefore suggesting that the hormone does not contribute to obesity. Additionally, those with anorexia nervosa have high levels of ghrelin compared with normal-weight controls, and in patients with cancer-induced cachexia, ghrelin levels tend to be higher. Similarly, patients with Prader-Willi syndrome-induced obesity have been shown to have high ghrelin levels related to increased food intake.

“We continue to learn more every day about the complexity of ghrelin and its isoforms,” Hillman said. “Additionally, it is known that ghrelin interacts with leptin and insulin sensitivity.”

Leptin and ghrelin are in opposing arms of food intake regulation. The experts who spoke with Endocrine Today said ghrelin appears to be the “hunger” hormone, whereas leptin appears to be the long-term signal that there are enough energy stores in the body.

“Understanding how both of these hormones work in a healthy state, as well as in pathological states, will have a major impact on the treatment and prevention of some weight-related disorders,” Hillman said.

Ghrelin for weight control/loss

According to Oral, the therapeutic potential for ghrelin remains to be explored, but she said the so-called hunger hormone may have clinical significance in anorexia or catabolic states.

After a meal, ghrelin is suppressed and then increases progressively during the postprandial phase to signal that it is time for the next meal; in short, ghrelin stimulates appetite. According to Garvey, if it is possible to block or antagonize ghrelin, it may be possible to decrease appetite and caloric intake to treat obesity.

“On the other side of the coin, if you can stimulate and make an agonist, you can stimulate the appetite, which may be beneficial in patients with anorexia or cachexia,” he said. “This is an interesting, potential drug target, but nothing is being brought to the stage in terms of clinical trials at the moment.”

Data from a cross-sectional report of 490 nondiabetic women from the Women’s Health Study who later developed type 2 diabetes demonstrated that ghrelin levels have an inverse relationship with BMI and with circulating leptin levels. According to the results, there was an inverse relationship between plasma ghrelin levels and BMI in the control subcohort and in the diabetes cohort across all quartiles of ghrelin levels (P<.0001 for all relationships). Ghrelin levels were also lower in women in the diabetes cohort vs. controls (429.1 ng/dL vs. 579.3 ng/L; P<.001).

Although the treatment of obesity with drugs targeted toward ghrelin may be effective in the short term, long-term maintenance may present a challenge, the experts suggest.

Yehuda Handelsman, MD, medical director and principal investigator of the Metabolic Institute of America and president of the American Association of Clinical Endocrinologists, said more research is needed to unveil the molecules that will block ghrelin or find areas where it works and block the effect of ghrelin.

Yehuda Handelsman

“Ghrelin is primarily a hormone that makes us want to eat. We know that if we block the effect of ghrelin, people may not be as hungry,” Handelsman told Endocrine Today. “Because ghrelin was identified relatively recently , much less is known about it.”

Leptin for lipodystrophy treatment

One role of leptin is its potential use in treating patients with certain metabolic disorders and rare forms of inherited or acquired lipodystrophy.

“Although [lipodystrophy] is a rare disease, it was historically a disease that disabled individuals and shortened lifespan. Leptin appears to work better than anything else we have in these patients and has been a real life changer,” Oral said.

To date, modified leptin in the form of metreleptin (recombinant methionyl human leptin) has been used to treat lipodystrophies. These studies were originally started as investigator-initiated studies at the NIH in 2000. These studies, targeting the most complicated lipodystrophy patients, led to the realization that metreleptin worked better than any other therapy in this rare condition. Metreleptin is believed to work by reducing fat accumulation in organs, thereby improving insulin sensitivity. In some subjects in clinical trials, metreleptin appeared also to decrease the hyperphagia that is often observed in patients with lipodystrophy.

“Leptin is a very short-lived protein that has to be modified to make it longer-lived in humans,” Garvey said.

Knowledge, however, of one’s levels could be used as a potential tool to personalize weight-loss methods. “Modified leptin has potential benefits in terms of treating lipodystrophy,” he said. “Some reports have shown that metabolism can be improved, as well as fat accumulation in the liver; there is improved glucose tolerance in diabetes and lower triglycerides as a consequence of treatment with modified leptin in patients with lipodystrophy.”

In December 2010, Amylin Pharmaceuticals initiated a rolling submission for a biologics license application with the FDA for the use of metreleptin to treat diabetes and/or hypertriglyceridemia in patients with rare forms of lipodystrophy. In April, the company submitted outstanding sections of the rolling submission and requested priority review by the FDA.

To date, metreleptin has been granted orphan drug designation in the United States to treat metabolic disorders such as diabetes and/or hypertriglyceridemia in patients with rare inherited or acquired forms of lipodystrophy, according to ChristianWeyer, MD, senior vice president of research and development at Amylin Pharmaceuticals.

Metreleptin therapy could substantially reduce high glucose and triglyceride levels in patients. There are no therapies currently indicated specifically for the treatment of metabolic abnormalities associated with lipodystrophy. If approved, it would be the first therapy indicated particularly for the treatment of diabetes and high triglycerides in patients with lipodystrophy, and the first approved therapeutic use of leptin, according to Weyer.

Metreleptin is currently available under an expanded access pathway in the United States and under compassionate use provisions in certain countries outside of North America.

Leptin also has a role in the regulation of insulin sensitivity and glucose/lipid homeostasis, besides effects on food intake, according to Oral, who is studying the effects of this hormone in liver fat accumulation. Other investigator-initiated studies to date have included the clinical investigation of metreleptin use among patients with type 1 diabetes.

Challenges remain, more research needed

One major challenge to weight-related disorders that demonstrates that the difference in ghrelin secretion can be used for intervention is the current form of ghrelin analogues —injection or infusion — which present difficulty in terms of clinical use, Hillman said.

“Not only in the practical aspect of logistics, but also among children and adolescents because the fear of needles is a major deterrent to their use,” she said.

As for ghrelin, the initial thought was that blocking it would promote weight loss, but studies have indicated that there may be a better chance of using ghrelin as an approach to treat type 2 diabetes, rather than as a stand-alone anti-obesity intervention. More research is needed on the potential adverse effects associated with the use of ghrelin analogues.

Furthest along in clinical development is the use of ghrelin-receptor agonists to increase gastrointestinal motility to treat conditions such as postoperative ileus and diabetic gastroparesis.

Many experts said leptin holds much promise when combined with other agents to promote weight loss, as well as in the development of super-potent leptin-receptor agonists, central nervous system–penetrant nasal leptin delivery systems and leptin-based agents to maintain weight loss among those who need it.

According to Oral, understanding the role of leptin within the hedonic system, its potential function in the brain regarding mood and memory, leptin resistance, and leptin’s potential use as adjunctive therapy rather than an alternative to insulin for type 1 diabetes are relatively new areas research is focusing on.

“There may be some promise with metreleptin in terms of promoting weight loss and preventing and reducing obesity when combined with other agents,” Garvey said. “I don’t foresee it happening in the near future.”

Research has also shown that leptin is permissive for pubertal development, involved in inflammation pathways, glucose metabolism and insulin sensitivity.

“Ghrelin’s therapeutic journey is still evolving,” Oral said. “Leptin has been studied for longer and it certainly changed from the ‘all-hopeful’ magic bullet for obesity to an important master regulator of energy homeostasis. Exactly what sort of a therapeutic role it will find in the clinic outside of its value in lipodystrophy remains to be seen.”

According to Endocrine Today Editorial Board member Samuel Dagogo-Jack, MD, A.C. Mullins professor in translational research and chief of the division of endocrinology, diabetes and metabolism at the University of Tennessee Health Science Center, experts are beginning to unravel the association between ghrelin and leptin and mechanisms of sleep that potentially affect human metabolism levels, but the data are still premature in those areas.

Samuel Dagogo-Jack

“We are just beginning to appreciate both of these hormones and the complexity of their roles,” Dagogo-Jack said. “In initial studies, it was disappointing that we couldn’t simply put leptin in the water and cure obesity, or use ghrelin to make people free from hunger, but that is transient in my opinion because future studies hold significant promise of breakthrough discoveries.”

Much research from various fields of medicine and science, including endocrine, neuroscience, obesity, addiction, psychiatry, behavioral medicine and other areas, is anticipated to shed light on the other roles these hormones play besides weight regulation.

Such discoveries, Dagogo-Jack said, will further explain the ghrelin and leptin pathways so that they can be used for treatment options.

“They are not currently ready for prime time, but I am highly optimistic that brilliant laboratories will find compounds to exploit these two mechanisms and give us some insight, or perhaps a solution, to the obesity epidemic. I urge physicians to stay tuned,” he said. – by Tara Grassia