Hedgehog protein blocks fat production, produces more bone

A protein that guides the early development of creatures as diverse as fruit flies and humans also plays a role in regulating fat and bone formation in adult organisms, researchers at UT Southwestern Medical Center have discovered.

The findings, reported in the January issue of the journal Cell Metabolism, open an avenue for potential therapy in humans for obesity, diabetes, osteoporosis and lipodystrophy, a disorder characterized by a selective loss of body fat.

The protein, called hedgehog, activates a series of biochemical reactions involving a host of other cellular proteins and genes. The complex interaction among these many components is called the "hedgehog signaling pathway," and it is critical that the pathway functions properly in the early stages of development of many organisms. Mutations in proteins that make up hedgehog signaling also are involved in some human cancers and other human diseases.

"We found that if you stimulate the hedgehog pathway in fruit flies, fat formation is blocked and the flies are skinny. If we block the pathway, the flies become obese," said Dr. Jonathan Graff, associate professor in the Center for Developmental Biology at UT Southwestern and the study's senior author. "We also found the same effects in mammalian models, specifically, in mouse cells. Activating the hedgehog pathway blocks fat from forming in mammals, while inhibiting the pathway stimulates the creation of more fat cells."

Dr. Graff and his colleagues also found that the hedgehog signaling pathway is altered in the fat tissue of obese mice. That finding might have implications for human health.

"Hedgehog signaling proteins are altered in either genetic obesity or diet-induced obesity, the kinds of obesity that most often affect humans," Dr. Graff said. In the obese mice, the researchers found less of the fat-inhibiting components of the hedgehog pathway.

The scientists who originally discovered the gene that produces the hedgehog protein named the gene based on the appearance of fruit flies that lack the gene. Without hedgehog signaling, the mutant fly larvae are covered with bristly hairs, and look like little rolled up hedgehogs.

A series of studies supports the notion that in mammals the hedgehog pathway instructs adult stem cells, telling them what to become.

"In mammals, it appears that hedgehog signaling regulates adult stem cells, diverting them from forming fat cells and redirecting them to become bone," Dr. Graff said. "Unfortunately, as humans age the opposite tends to happen. That is, the amount of bone cells that we have decreases, while the amount of fat cells we have increases.

"Perhaps as we age, hedgehog signals become blocked or decreased. This study implies that if we block hedgehog signals, humans would have less bone and more fat. Conversely, if we can activate the pathway, we might be able to prevent or reverse osteoporosis and simultaneously prevent or reduce fat accumulation," he said.

Dr. Graff said that other researchers have spent a great deal of effort developing agents to regulate the hedgehog pathway. These agents, currently in the early development phase for anti-cancer treatments, hold promise for human use.

"The drugs already in clinical development might be useful for this purpose as well," Dr. Graff said. "If medicine could stimulate the hedgehog pathway in adults, those adults could potentially not only get leaner and become more fit, but could also add bone mass as well. That could affect obesity, diabetes, lipodystrophy and osteoporosis, all of which are major human diseases."

Dr. Graff cautioned that because the hedgehog pathway is so involved in many biological processes, side effects are possible. However, agents could be developed to target hedgehog therapies to specific human tissues, such as fat or bone, he said.

"There are still tremendous hurdles to overcome before a treatment or a drug is developed," Dr. Graff said. "We have to do the basic research before we even know what those hurdles are."

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UT Southwestern researchers from the Center for Developmental Biology involved in the work are lead paper authors Jae Myoung Suh and Xiaohuan Gao, student research assistants; postdoctoral researchers Drs. James McKay and Renee McKay; and undergraduate Zack Salo.

The research was funded by the National Institutes of Health, the American Cancer Society and the Leukemia and Lymphoma Society.

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