ANN ARBOR, Mich. – High levels of leptin, a hormone produced by fat cells in the body, could explain why obese people develop dangerous blood clots -– which can cause heart attacks and strokes – more often than people who are not overweight.
The association between obesity and blood clots is well known; but the cause has remained a mystery. Now, new research with mice conducted by scientists at the University of Michigan Medical School and published in the April 3 issue of the Journal of the American Medical Association, indicates that leptin may be responsible.
“Our results suggest that clot formation begins with some type of interaction between leptin and the leptin receptor on platelets – blood cells which stick together to make clots,” says Daniel T. Eitzman, M.D., a cardiologist at the U-M Cardiovascular Center and an assistant professor of internal medicine in the Medical School.
Knowing how to block this leptin-receptor interaction could help prevent heart attacks and strokes in people who are either obese or overweight, which is half the adult population of the United States.
According to Eitzman, leptin released by fat cells regulates body weight in part by suppressing appetite. When leptin levels in blood go up, the brain signals us to stop eating. But the system breaks down for those who are grossly overweight. Since they have more and larger leptin-producing fat cells than thinner people, their leptin levels increase substantially with every pound of additional weight gain. When leptin reaches very high levels in the blood, Eitzman explains, obese people become resistant to leptin’s signal – making them increasingly vulnerable to leptin-induced blood clotting.
While it certainly plays a major role, Eitzman emphasizes that leptin may not be the only factor involved. “The link between obesity and cardiovascular disease is very complex, and there is much we don’t know about how other blood clotting factors are regulated in obesity,” he says.
Eitzman’s discovery of the relationship between leptin and clotting was a lucky accident. Originally, he had no intention of focusing on leptin at all. He just wanted to examine how obesity affects blood clot formation. So he decided to use the fattest laboratory mice he could find – a strain of mutant mice that just happened to be missing the gene required to produce leptin.
When Eitzman began his experiments, the first results were surprising. Contrary to his expectations, leptin-deficient obese mice took nearly twice as long (an average of 75.2 minutes) to form blood clots as normal mice (42.2 minutes). Eitzman ran his experiment again -- this time using a different strain of obese mice, which were missing the gene for the leptin receptor. These mice also took an abnormally long time to clot (68.6 minutes).
“Finally we tried injecting the mice with leptin, and that’s when clotting times in the leptin-deficient mice dropped to normal [41.8 minutes],” said Eitzman. “That’s when we first knew that leptin was the critical factor. To confirm our results, we transplanted bone marrow from leptin-deficient to normal mice. When the transplanted bone marrow began producing platelets without the leptin receptor, clotting time in the normal mice was prolonged significantly.”
Recent research by other scientists found evidence for leptin’s role in human blood clotting. Results from the West of Scotland Coronary Prevention Study, published in the December 2001 issue of Circulation, showed that high levels of leptin were an independent risk factor for cardiovascular thrombotic events, such as heart attacks and strokes, in 1,160 men enrolled in the prospective study.
“We suspect that the more leptin in blood plasma, the higher the risk of forming blood clots, but we haven’t quantified the relationship yet,” Eitzman says. “We know that losing weight lowers the amount of leptin in your bloodstream, however. So for now diet and exercise remain the best way to prevent blood clots and the strokes and heart attacks they cause.”
Eitzman and his research team also are studying the relationship between leptin and insulin sensitivity to try to discover why diabetics have a higher-than-normal risk of blood clots.
This study was funded by the National Institutes of Health. Other U-M Medical School researchers involved in the study included Peter F. Bodary, Ph.D., the paper’s lead author, who is now at the University of Toledo; Randal J. Westrick, graduate student; Kevin J. Wickenheiser, undergraduate; and Yuechen Shen, M.D., research associate.
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