OHSU Researchers Identify Brain Circuitry in Mouse Model Responsible for Cachexia

02/13/01    Portland, Ore.

Discovery Also May Aid Development of Anti-Obesity Drugs

It's one of the side effects of cancer and AIDS that can pose major hurdles for physicians hoping to prescribe aggressive treatment. Cachexia is a state of malnutrition or wasting away. The condition is characterized by a loss of appetite and increased metabolism. This results in a reduction of fat and muscle mass making weight gain difficult for patients with these diseases, especially children and the elderly. Now researchers at Oregon Health Sciences University have located a mechanism in the brain that plays a major role in cachexia. The research is printed in the Feb. 15 edition of Cancer Research. Daniel Marks, M.D., Ph.D., is lead author of the article. Marks currently is serving a fellowship in pediatric endocrinology at OHSU. The research was conducted in a lab directed by Roger Cone, Ph.D., a senior scientist at OHSU's Vollum Institute and senior author of the paper.

To track cachexia to a specific region of the brain, OHSU researchers targeted a group of receptors, known as the MC4 receptors in a portion of the hypothalamus. In the past this area of the brain has been linked to obesity.

"Previous research has shown that decreased activity in these nerve cells causes a person's metabolism to slow and their appetite to increase, causing weight gain. Right now, the MC4 receptor is one of the major targets of the pharmaceutical industry for the treatment of obesity. However, we hypothesized that if this group of nerve cells worked too well, the result for that animal would be the opposite - a higher metabolism and low appetite, or cachexia," said Cone.

To test the theory that the same group of cells could control both weight loss and weight gain, OHSU scientists utilized cancer and infectious disease models in mice. As predicted, these led to a cachexic state, causing weight loss. In gene knockout mice bred with inactive MC4 receptor cells, or when the receptor was blocked by drug administration, the animals resisted weight loss due to illness. In addition, researchers found that agouti-related protein (AGRP), provided by co-author and collaborator Nicholas Ling, Ph.D., at Neurocrine Biosciences Inc., which is known to slow the activity of MC4 receptor cells, caused mice with an experimental form of cachexia to hold their weight.

"In many AIDS and cancer patients, cachexia can be a major factor in determining how long a person will live and what their quality of life will be like," explained Marks. "Hopefully, continued research will provide medications that can halt or slow the progression of cachexia, therefore prolonging lives. The absence of cachexia in AIDS and cancer patients would allow physicians to use a wider range of therapies including aggressive treatments like radiation and chemotherapy. In addition, this research provides additional information about the brain's influence on weight gain and weight loss."