Molecule linking two hormones effectively treats obesity in mice
By Leon Gettler
December 20, 2012
With health authorities saying the world is facing an obesity epidemic and with a recent major study finding that – for the first time – more people now die from obesity-related illnesses like heart attacks and strokes than malnutrition, scientists have been tackling the fat problem.
Recent approaches to this problem include looking at ways to slow down the biological clock and converting calorie-storing white fat cells into heat-generating brown fat cells. Now, a new study has found that linking two hormones into a single molecule could lead to improved treatments for medical conditions such as obesity.
The research was carried out by chemistry professor Richard DiMarchi at Indiana State University and Matthias Tschop, professor of medicine and director of the Institute of Diabetes and Obesity, Helmholtz Center Munich, Germany.
The findings show that the female steroid estrogen, which enters cells and directly affects nuclear DNA, can be engineered to be more effective in treating obesity and diabetes by combining it with glucagon-like peptide 1, or GLP-1, creating a single molecule with fewer side effects.
GLP1, a peptide hormone from the digestive system, is used in drugs to treat Type II diabetes. These drugs improve blood sugar control and can lead to some weight loss, but not enough to be used as weight-loss drugs. Similarly, estrogen is another hormone that can cause weight loss by regulating receptors in the brain but its side effects increase the risk of cancer, particularly of breast and ovarian cancers. As a result, it is not really used for weight loss.
DiMarchi and Tschop combined the GLP1 with estrogen in obese lab mice and found that the combination was more effective in producing weight loss than when used on their own. The GLP1, they found, acted as a “medical chaperone” for the estrogen, taking it to the hypothalamus and pancreas which metabolize foods. The precise targeting and synergy between the peptide and steroid hormone in combination as a single molecule reduced the likelihood of the estrogen producing cancers or growing tumors.
"We find that combining the hormones as a single molecule dramatically enhanced their efficacy and their safety," DiMarchi said. "The combination improves the ability to lower body weight and the ability to manage glucose, and it does so without showing the hallmark toxicities associated with estrogen."
The research also opens the possibility of targeted steroid hormones being used to treat other diseases, where side effects had prevented therapeutic use in the past.
The next obvious step for DiMarchi and his researchers is to test other combinations of peptide and steroid hormones to see how broad an approach medicine can take in treating conditions. There is still a lot they don’t know about how they can work together and whether it’s safe.
DiMarchi says research will continue to focus on the biological action and identifying a suitable drug that can be used in further studies on humans.
The team's study has been published in Nature Medicine.
Source: Indiana University
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