Scientists have produced severely overweight mice with dirty blonde coats and developed a treatment method designed to help them lose their excess weight, leading to new answers about human obesity and future treatments to arrest it.
These genetically engineered mice, developed by Ute Hochgeschwender of the Oklahoma Medical Research Foundation in Oklahoma City and Miles Brennan of the Eleanor Roosevelt Institute in Denver are lacking the POMC gene and all the peptides processed from this gene. POMC deficiency was discovered only last year in patients as a cause of severe obesity. The researchers’ findings are published in the September issue of the journal Nature Medicine.
The mutant strain of mice model human patients with the POMC deficiency, which causes severe obesity, glucocorticoid deficiency and red hair. The development of an animal model for this inherited type of obesity offers two major benefits, the authors say. Extensive research can now be done into the physiology and mechanisms of the condition as well as testing for future treatment regimens.
“The obese mice were injected daily with alpha-MSH, one of the missing peptides, and after two weeks the mice lost 46 percent of their excess weight,” said Hochgeschwender. The weight loss, she emphasized, is not simply a change in appetite, but also in fat storage. The researchers have found that mice lacking POMC store excess fuel uptake rather than burning it like normal mice.
“In POMC-deficient humans and mice, no MSH is being made,” said Hochgeschwender. “Incoming fat is taken up and is stored in the body, resulting in overweight. Even though the body is signaling to the brain that there is too much fat on board, the brain does not have the signal to respond and stop the further uptake and storage of fat.”
For treating human obesity, the authors expect melanocortins to be effective in POMC-deficient patients. Preliminary results in mice with other forms of obesity look promising.
“Melanocortin could very well turn out to be a good anti-obesity drug,” said Hochgeschwender. “We hope to pair with a strategic partner that will help to move these studies into clinical trials soon. If this process works in humans, we hope to get it to the public in the most efficient and timely way possible.”
This is “an important step forward, ” said Dr. Greg Barsh, of Stanford University, writing in the “News and Views” editorial section of Nature Medicine. In attempts to develop melanocortin-like compounds as therapeutic agents for human patients “the POMC knockout mice will provide an invaluable system for testing such compounds.” In addition to the importance for obesity research the POMC-deficient mice “promise surprising new insights likely to impact on several areas of biology and medicine.”
The Oklahoma Medical Research Foundation is a private, non-profit biomedical research institute founded in 1949, with major research emphasis on heart disease, cancer, Alzheimer’s disease, autoimmune diseases, AIDS, diabetes and children’s diseases.
