May 13, 2004 DENVER -- In 1999, Drs. Miles Brennan and Ute Hochgeschewender announced their finding that melanocyte-stimulating hormone (MSH) regulates the balance of fat storage and metabolism. In April, they received a patent on the use of MSH analogs -- chemicals that mimic MSH -- as potential treatments for obesity (U.S. Patent #6,716,810).
Brennan is an associate research professor at the Eleanor Roosevelt Institute at the University of Denver (ERI) and Hochgeschwender is an associate member of the Oklahoma Medical Research Foundation. Their research also suggests that MSH integrates fat and glucose metabolism in the periphery, or body. The scientists began by engineering mice missing the pro-opio melanocortin (POMC) gene. The mice, which had no MSH in their bloodstream, became obese because they stored all the fat they ate without metabolizing any of it.
"We were then able to reduce their weight by adding MSH back into the peripheral circulation," says Brennan. "There are MSH receptors in essentially all peripheral tissues, and we know that mice treated with MSH experience an increase in the level of free fatty acids in the bloodstream. What we think happens is that MSH causes the adipocytes, or fat cells, to release free fatty acids, while other cells are stimulated to remove them from the bloodstream and burn them. Essentially it's a way to mobilize your stored fat for current needs."
The animals experienced no apparent ill effects with the weight loss. "The MSH has the highest activity when you have the highest level of excess weight," Brennan explains. "As the animal approaches normal weight, the effect plateaus out -- this is not going to be the anorexic's drug of choice, because when there's no more stored fat, you can't change the balance. We think it's got significant potential for obesity therapies."
MSH research pioneer Victor Hruby, agrees. "It's clear that the POMC gene and its products are involved in additional ways that Miles and his colleagues have discovered, such as feeding behavior and energy homeostasis. It continues to be an evolving, exciting story that has many implications for human health. I think they are on to something worth pursuing."
The Regents Professor in the University of Arizona Department of Chemistry, Hruby also is a professor of neuroscience, biochemistry and molecular biophysics at the university and the Arizona Research Laboratory. He and his collaborators began studying MSH in the 1970s, and have developed several hundred derivatives of the hormone over the past 35 years.
"I tell my students we're living in a revolutionary time," he says. "Who knows what we'll discover tomorrow, because it's clear there are lots of unknowns. It gets more exciting all the time, and I feel almost like I'm starting over again."
The next step is licensing the discovery and working with a pharmaceutical company to develop and test clinical therapies. Previously, Brennan and Hochgeschwender, who have collaborated since 1986, have patented mice with a range of genetic modifications to the POMC gene (U.S. Patent # 6,603,058), and a method of reducing insulin resistance (U.S. Patent #6,689,938) that could lead to potential treatments for diabetes accompanying obesity.
Denver's Eleanor Roosevelt Institute (ERI) was founded in 1961 as a private, independent research center. ERI merged with the University of Denver in 2003. The Institute is staffed by leading scientists from around the world who study Down syndrome, Lou Gehrig's disease, cancer, obesity, type II diabetes and other diseases and conditions. It is the mission of the Institute's scientists to seek an in-depth understanding of the process of life and through this understanding, work towards unlocking the mysteries of human health and disease.
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