Activating the hedgehog pathway protects mice from obesity

Boosting a protein signaling pathway in the body known as "hedgehog" prevented weight gain in mice, a team from Washington University in St. Louis found. The method, which stops fat cells from growing larger, targets a common cause of obesity in adults. 

The hedgehog signaling pathway is well-known to oncology researchers. The Washington University team focused on the pathway specifically in fat cells, engineering mice with genes that activated it in those cells when they ate a high-fat diet. After eight weeks on the diet, control mice with unaltered hedgehog pathways became obese, while the engineered mice did not gain any more weight than control mice fed a normal diet did. 

As it turned out, stimulating the hedgehog pathway inhibited the size of the fat cells, said senior investigator Fanxin Long, Ph.D., a professor of orthopedic surgery at Washington University. Specifically, it prevented the cells from collecting and storing fat droplets. 

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Children may put on weight through an increase in their number of fat cells, but this number stays constant in adults. Instead, adults gain or lose weight because of changes in the size of their fat cells. 

"What's particularly important is that the animals in our study ate a high-fat diet but didn't gain weight," Long said in a press release, "and in people, too much fat in the diet is a common cause of obesity." 

The findings, which appear in eLife, are promising, but might be challenging to translate to humans. Abnormal activation of the hedgehog pathway is implicated in a number of human cancers, including brain, lung, breast and prostate cancers. Researchers are, in fact, developing inhibitors for the pathway to be used against childhood brain tumors and the rare disease, Gorlin syndrome, which increases a person's risk of developing cancerous and noncancerous tumors in multiple parts of the body. 

Long cautions that any attempt to activate the hedgehog signaling pathway would need to be done carefully to avoid unwanted side effects. But because the pathway works similarly in mice and people, he's hopeful it will prove feasible to target it only in fat tissue, as his team did in this study. "This could lead us to a new therapeutic target for treating obesity," he said.