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
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
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
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;
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.
“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
“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
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
“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
“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
“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
- Dr. Garvey serves on the advisory boards of Vivas Liposcience and is on the speakers’ bureau for Merck. Dr. Handelsman served as an adviser to Amylin. Dr. Oral has received research support from Amylin and the NIDDK. Dr. Weyer is an employee of Amylin and a shareholder of the company. Drs. Dagogo-Jack and Hillman report no relevant financial disclosures.