Researchers at the Massachusetts General Hospital (MGH) have found a powerful link between leptin, the so-called obesity hormone, and the beta cells of the pancreas, which produce insulin. Their findings may help unravel the mystery of how leptin is related to human obesity and could point to a role for the hormone in the development and possibly the prevention of non-insulin-dependent diabetes mellitus (NIDDM). The study appears in the June issue of Diabetes.
The researchers studied the effect of leptin on beta cells from mice with genetic defects that cause obesity and diabetes. These mice have mutations in the genes that code either for leptin or the leptin receptor -- a molecule that receives the leptin signal. In contrast to normal mice, whose insulin levels drop when they have not eaten recently, mice with these mutant genes develop hyperinsulinemia -- excessively high blood insulin levels -- when fasting. The condition disappears when the mutant mice are treated with leptin.
The MGH-led group found that leptin directly reduces insulin secretion in the beta cells of mice with hyperinsulinemia. This observation is particularly provocative because, in humans, fasting hyper-insulinemia is a risk factor for NIDDM, as well as for cardiovascular disease. They also found that leptin suppresses insulin secretion by interacting directly with receptors on the beta cells, activating a structure called an ion channel. This type of ion channel -- called an ATP-sensitive potassium channel -- is known to be a key component in the process by which the pancreas secretes insulin in response to increased blood sugar levels.
Earlier studies by the MGH group and others showed that leptin receptors were found in the pancreas and might be involved in insulin secretion. This most recent study is the first to confirm that leptin acts directly on the insulin-producing beta cells and to identify the molecular mechanism involved. "We believe that leptin is part of a hormonal communication system between the pancreas and the body's fat stores," says study leader Joel F. Habener, MD, of the Laboratory of Molecular Endocrinology and the Howard Hughes Medical Institute at the MGH. "A problem in that communication system could be a key step in the development of NIDDM, which makes sense because we know that obese people are at risk for this disorder."
The researchers also propose that treatment with leptin or leptin-sensitizing drugs may help prevent the development of diabetes in obese individuals who exhibit fasting hyper-insulinemia. Even though these individuals already have elevated leptin levels, administration of additional leptin may help suppress the overproduction of insulin that is believed to eventually wear out the beta cells, triggering NIDDM.
When scientists first announced the discovery of the ob (obesity) gene and its protein product leptin in 1995, it was thought that mutations in this gene might directly cause much human obesity. However, it soon was determined that obese humans -- in contrast to the mutant mice in which the gene was discovered -- had normal leptin genes. In fact, leptin levels in obese humans were higher than those in slim humans. Attention then turned to the leptin receptor, with the thought that obese humans somehow were resistant to the hormone's effects, just as those with NIDDM are resistant to insulin. No defect, however, has been found in any human leptin receptor.
Habener explains that the defect may exist in the series of reactions set off inside a cell after a receptor has been activated by leptin. "It's as though leptin was the car key and the receptor was the ignition," he says. "Both of those could be fine, but if there's a problem somewhere in the car's wiring, it won't start. We don't yet know where the glitch is, but with more information about how leptin interacts with cells, we have a better shot at finding the defect."
In addition to its action on the pancreatic beta cells, leptin also acts on receptors in a part of the brain called the hypothalamus, where it controls appetite, a process that appears to break down in obese people. When scientists discover the defect in the leptin-based communication between fat cells and beta cells -- which are more accessible and may be easier to study than brain cells -- they may be able to track down a similar defect in leptin's activity on the hypothalamus, finally pinpointing the hormone's elusive role in human obesity. Habener and his colleagues do not expect that any kind of leptin-based weight-loss treatment will eliminate the basic need for obese people to restrict calories and increase activity. In fact, they suspect that the first step in the process leading to breakdown of the normal leptin-controlled systems is accumulation of too much body fat through overeating and lack of exercise.
"Throughout most of history when calories were scarce, it would have been an advantage to inherit a genetic makeup that induced the body to store calories as fat," he says. "But today, when calories are readily available, those 'thrifty' genes become a problem. As the body stores excess fat, which in turn produces excess leptin, the body's normal response to leptin may break down, leading to even more fat accumulation and possibly to the hyperinsulinemia that precedes NIDDM."
Habener is a professor of Medicine at Harvard Medical School and a Howard Hughes Medical Institute investigator. His coauthors on this study are Timothy Kieffer, PhD, Scott Heller, PhD, and Colin Leech, PhD, of the MGH Laboratory of Molecular Endocrinology, and George Holz, PhD, of the MGH Diabetes Unit.
The Massachusetts General Hospital, established in 1811, is the oldest and largest teaching hospital of the Harvard Medical School and conducts the largest hospital-based research program in the United States. The MGH has major research centers in transplantation biology, the neurosciences, cardiovascular research, cancer, cutaneous biology and photomedicine. Along with Brigham and Women's Hospital, the MGH is a founding member of Partners HealthCare System, Inc.
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