Hedgehog Protein Update News

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Hedgehog Protein Blocks Fat Production, Produces More Bone

http://www.medicalnewstoday.com/medicalnews.php?newsid=36023

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. 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. "

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. McKay and 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.

This news release is available on our World Wide Web home page at

utsouthwestern.edu/home/news/index.html