University of Texas Southwestern Medical Center researchers found an endocrine hormone used in clinical trials as an anti-obesity and anti-diabetes drug causes rapid bone loss in mice, raising concerns about its safety.
The hormone, fibroblast growth factor 21 (FGF21), promotes bone loss by enhancing the activity of a protein that stimulates fat cells but inhibits bone cells. “This hormone is a very potent regulator of bone mass,” says Yihong Wan, MD, assistant professor of pharmacology. “When we oversupply FGF21 in mice, it results in substantial bone loss.”
The scientists were investigating the hormone’s properties since its discovery in 2005 as a potential drug. Bone loss was a side effect of another class of compounds that had been commonly used in the treatment of diabetes—activating the same protein in a manner similar to FGF2—and leading the research team to investigate the bone effect of FGF21 in three kinds of mice.
They found that rodents fed a drug form of the hormone over a two-week period lost 78% of their spongy bone. Mice engineered to produce excess FGF21 had similar effects. Conversely, researchers found mice completely lacking the hormone had comparable gains in bone mass.
While the insulin-sensitizing effects of FGF21 make it a potentially powerful anti-obesity drug, that could be canceled out by risk of osteoporosis and fractures associated with bone loss. “The bone effect is clear,” says David Mangelsdorf, chairman of pharmacology, a Howard Hughes Medical Institute investigator at UT Southwestern. “It’s a tradeoff of benefits and risks, and the key will be to design the drug in such a way to leverage the two against each other, dialing out the side effects and dialing in the positive.”
The researchers identified how FGF21 regulates the activity of a diabetes-fighting compound in fat tissue, altering metabolism in response to starvation and resumed eating for survival-driven energy conservation
“FGF21 helps mobilize the fat in adipose tissue back to the liver and burn it. But when the animal is refed, it stops this process and immediately turns back to restoring fat. In one case, it turns this system on, and in the other, turns it off,” says Steven Kliewer, MD, professor of molecular biology and pharmacology.
The study was published online in the Proceedings of the National Academy of Sciences.
Release Date: Feb. 6, 2012
Source: University of Texas Southwestern Medical Center
