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Leptin as a treatment for generalized lipodystrophy: a translational success story

In 1949, researchers identified a new mouse model that was extremely obese. Little did they know that research on that obese mouse would lead—65 years later—to an approved medical treatment for people who lack fat tissue altogether.

But, that is exactly what happened, after many decades of research that included the discovery of a hormone called leptin. The translational success was a result of collaborations among many scientists, including NIDDK-supported scientists at universities, scientists in the NIDDK Intramural Research Program, industry researchers, and many others. This story demonstrates how exciting discoveries in the laboratory provide the foundation for improving the health of people.

The Obese Mouse and the Discovery of Leptin

Scientists who identified the obese mouse model in 1949 called the unknown gene causing the obesity “ob.” By the 1980s, the identity of the ob gene was still a mystery, but it was becoming more and more apparent that research on genetic contributors to obesity was critically important to pursue. Therefore, the NIDDK sought to support research to identify obesity-related genes in rodents, including the ob gene. The Institute sponsored a workshop on this topic and developed an initiative to solicit research applications.

In 1989, the NIDDK awarded a grant to Dr. Jeffrey Friedman through this initiative. Dr. Friedman’s subsequent pioneering research led to the 1994 discovery of the mouse ob gene. The hormone produced by this gene was named “leptin,” a term that derives from a Greek word meaning thin. Because the ob mutant mouse was obese, the scientists realized that the normal ob gene—and the hormone it encodes—must contribute to leanness.

The landmark discovery of leptin unleashed a wave of new research advances in fat biology and metabolism. Researchers found that leptin is secreted by fat cells and released in proportion to the amount of fat. These observations drastically altered the prevailing view of normal fat tissue as simply a metabolically passive “fat storehouse.” Research fueled by this 1994 discovery also led to the identification of a number of other substances that, like leptin, are secreted by fat cells and influence appetite and metabolism.

Studies demonstrated that obese animals deficient in leptin, including mice carrying the mutant form of the ob gene, lost weight when given the hormone. Therefore, researchers postulated that leptin treatment might also be useful for human obesity. There are, in fact, very rare instances of complete deficiency of leptin in humans that result in morbid obesity from infancy. Leptin treatment in these individuals caused substantial weight loss, providing hope for improved quality of life and longevity.

Unfortunately, in clinical studies done at that time, leptin administration was not effective in treating the vast majority of cases of human obesity, which are not due to leptin deficiency. In most cases, obesity results from a complex interaction among an individual’s genes and the environment. Obese individuals, in fact, usually have very high levels of leptin, probably a consequence of the many fat cells secreting it. The inability of the high levels of leptin to decrease body weight suggests that the more common forms of obesity are associated with a resistance to leptin’s actions. Although these results were disappointing, scientists did not give up in their quest to use this new knowledge to benefit people.

Testing Leptin as a Treatment for Lipodystrophy

Scientists in the NIDDK’s Intramural Research Program had broad experience with respect to studying people with various forms of insulin resistance. Using this experience and knowledge, they identified a patient population—people with lipodystrophy—who could potentially benefit from leptin treatment.

Lipodystrophy is actually a group of disorders with disparate origins but with a common set of metabolic consequences. Lipodystrophy can either be genetic or acquired, and can be generalized (near total lack of fat) or partial (fat loss in certain parts of the body). While lipodystrophy is characterized by the loss of fatty tissue in certain areas of the body, tissues such as liver and muscle exhibit significant abnormal accumulation of fat, which impairs metabolic activity. People with the disorder also exhibit resistance to the effects of insulin and are thus at high risk of developing diabetes. They may also have a range of lipid abnormalities.

Treatment of lipodystrophy has included the administration of insulin, oral hypoglycemic (blood glucose [sugar]-lowering) agents, and lipid-lowering drugs. Even with treatment, people with lipodystrophy continue to have severely high levels of triglycerides, leading to recurrent attacks of acute inflammation of the pancreas; severe problems controlling blood glucose levels, posing risks of developing diabetic complications; and fat accumulation in the liver, which can result in cirrhosis and liver failure.

Because many people with lipodystrophy have low leptin levels due to the lack of fat cells that produce the hormone, and because research had demonstrated beneficial effects of leptin on insulin sensitivity and fat metabolism in a number of tissues, researchers in the NIDDK Intramural Research Program and their collaborators, including major collaborators at the University of Texas Southwestern and Yale University, investigated whether leptin treatment could ameliorate conditions associated with lipodystrophy.

Results from two small clinical studies testing this hypothesis were published in 2002. The studies showed that short-term leptin therapy (3 to 8 months) had dramatic benefits in individuals with lipodystrophy. In one study of females with different forms of lipodystrophy, most of whom also had diabetes, leptin therapy improved blood glucose levels, lowered triglyceride levels, and decreased liver fat content. In another study, leptin therapy markedly improved insulin sensitivity, lowered lipid levels, and decreased liver fat content in individuals with severe lipodystrophy who also had poorly controlled diabetes. Participants in these studies were able to reduce or discontinue their diabetes medications.

Seeing such dramatic results, researchers next examined the effect of longer-term leptin therapy. In results published in 2005, the researchers found that in 15 people with severe forms of lipodystrophy and poorly controlled diabetes, 12 months of leptin treatment led to improved blood glucose and blood lipid levels, and decreased fat in their livers. Participants also reported a dramatic reduction in their appetite, which led to moderate reductions in their weight. In addition, they were able to discontinue or reduce their diabetes medications. In 2010, the scientists reported similarly remarkable results in 35 participants treated with leptin for 12 months.

The scientists also examined the effect of leptin on other metabolic abnormalities associated with lipodystrophy. For example, females often have irregular or absent menstrual cycles; leptin treatment was found to correct that condition. Leptin treatment was also highly effective in treating people with lipodystrophy and nonalcoholic steatohepatitis (NASH), a progressive metabolic liver disease. In a study of 25 people, researchers found that a surprisingly high number had some form of kidney disease; leptin treatment was found to improve their kidney function. Thus, leptin corrected a broad range of metabolic defects associated with lipodystrophy.

Because lipodystrophy is a chronic condition, it was important for the researchers to study whether leptin treatment was safe and effective to use as a long-term treatment. In 2011, they reported the results of a study of 55 people with lipodystrophy who were treated with leptin for 3 years: the participants had robust and sustained improvements in their blood glucose and blood lipid levels, and also had improvements in markers of liver function, a sign that the excess fat in their livers had likely diminished. Importantly, there were few adverse reactions to leptin during the study. Together, these data suggest that leptin is a safe and highly effective treatment for people with lipodystrophy.

Leptin Is Approved as a Treatment for People with Generalized Lipodystrophy

As a result of the clinical studies described above, in 2010, the industry collaborator that provided the leptin used in the studies—Amylin Pharmaceuticals/ Bristol-Myers Squibb/AstraZeneca—began the process to submit a “biological license application” to the U.S. Food and Drug Administration (FDA) seeking approval to use leptin (marketed as Myalept™) as a treatment for people with lipodystrophy; the application was completed in 2012. The primary data used in the application were directly from the NIDDK’s clinical studies.

In February 2014, the FDA made the exciting announcement that it approved Myalept™ for treating people with generalized lipodystrophy—whether genetic or acquired—in addition to following a healthful diet. Of note, leptin treatment helps people with lipodystrophy follow a healthful diet. Without leptin, they are always hungry; leptin treatment dramatically reduces their appetite and thus also decreases their food intake.

Leptin is the first approved therapy that is indicated for people with generalized lipodystrophy. People may still need to take conventional medicines (e.g., lipid-lowering drugs or insulin), but required dosages of those medicines are markedly lower while taking leptin. In particular, people are often able to discontinue insulin use.

The FDA approval of leptin represents a much-needed treatment for people with generalized lipodystrophy—a rare and life-threatening disorder for which available therapies were only partially effective and did not address the underlying cause of the metabolic abnormalities, leptin deficiency.

A Team Effort Leads to a Research Success Story

The clinical studies testing leptin therapy for lipodystrophy conducted by the NIDDK Intramural Research Program—and used as the primary scientific basis for FDA approval—required numerous collaborators and spawned new collaborations. Leading this effort was Dr. Phillip Gorden, a former NIDDK Director who returned to the laboratory to continue his research. Because the leptin used in the research was manufactured by industry, the Intramural Research Program and the NIDDK Technology Advancement Office worked with industry to obtain the leptin needed for the studies. In addition, because lipodystrophy affects the liver and kidneys, scientists in the Intramural Research Program with expertise studying those organs were valuable contributors to the studies. Furthermore, collaborators external to the NIDDK have studied the underpinnings of different forms of genetic lipodystrophy; several genes have now been identified. Finally, many of the study participants were evaluated and treated at the NIDDK’s Metabolic Clinical Research Unit, a facility in the NIH Clinical Center that enables scientists to make precise metabolic measurements. It was only through the contributions of all of these collaborators that this translational success story came to fruition.

Looking to the Future

As described in this story, knowledge gained from studying a common condition, obesity, led to the discovery of leptin and a treatment for a very rare disease, generalized lipodystrophy. Scientists are now coming full circle by building on the successful clinical studies with leptin in lipodystrophy and applying that knowledge to research on common diseases. For example, by studying women with lipodystrophy, scientists in the NIDDK Intramural Research Program are also gaining insights into a more common condition: polycystic ovarian syndrome (PCOS). PCOS is a set of symptoms that results from a hormonal imbalance; it affects females of childbearing age and is the most common cause of anovulatory (absence of ovulation) infertility. Women with lipodystrophy have features of PCOS, which are improved by leptin therapy. This observation suggests that knowledge gained by studying women with lipodystrophy may provide understanding of the more complex and common PCOS and shed light on improved ways to treat it.

NIDDK-supported scientists are also gaining important insights into leptin’s biological functions, which are informing future research. For example, NIDDK-supported extramural researchers found that after people lost 10 percent of their body weight, their leptin levels and metabolic rate decreased, resulting in a metabolic state that favors weight regain. Researchers discovered that leptin replacement after weight loss increases people’s metabolic rate to the pre-weight loss level. Although it is not yet known whether giving people leptin could help maintain weight loss, the findings suggest the need for future research to develop novel therapies to support weight loss maintenance.

Other NIDDK-supported researchers are exploring leptin’s use in treating other diseases and disorders. For instance, NIDDK-supported extramural researchers found that leptin treatment improved the health of women with a condition called hypothalamic amenorrhea (absence of a menstrual cycle due to excessive exercise or stress, or inadequate food intake), which can result in infertility and bone loss. In women with this condition, leptin treatment restored menses and ovulation, independent of weight gain. In addition, researchers in the NIDDK Intramural Research Program studied people with a rare genetic syndrome caused by mutations in the gene encoding the insulin receptor, which results in extreme insulin resistance; people with this syndrome have a very difficult time controlling their blood glucose levels. In a small study, the researchers found that leptin treatment improved patients’ blood glucose levels. These studies have identified other populations who may possibly benefit from leptin treatment.

Through future research, it is also important to identify safe and effective treatments for people with other forms of lipodystrophy, including rare forms of partial lipodystrophy, as well as a more common form of lipodystrophy that is acquired from taking certain types of medications for human immunodeficiency virus (HIV). While leptin was approved for a rare form of lipodystrophy, partial forms of the disorder are more common and additional research is needed to identify others who might benefit. Thus, future research is needed to identify therapies to improve the health of all people with lipodystrophy.


The FDA approval of leptin for generalized lipodystrophy is a culmination of decades of research—NIDDK-supported basic research that led to the discovery of leptin, as well as clinical research conducted by scientists in the NIDDK Intramural Research Program and their collaborators testing leptin in people. People with lipodystrophy were not originally envisioned as a group who would benefit from leptin treatment, as leptin was first thought to be a promising treatment for common forms of obesity. But, because of the dedication of numerous scientists and clinical trial volunteers, people with generalized lipodystrophy have a new FDA-approved treatment. It is a translational success story representing the ultimate goal of NIDDK-supported research—to improve people’s health and quality of life.

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