Wrinkle-free Mice Provide Clues About Obesity, Wrinkles And Hair Growth

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Web Site:      ScienceDaily Magazine

Page URL:   http://www.sciencedaily.com/releases/2003/04/030409075417.htm

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Original Source:   Washington University School Of Medicine

Date Posted:         2003-04-09

Wrinkle-free Mice Provide Clues About Obesity, Wrinkles And Hair Growth

St. Louis, April 2, 2003 -- What do wrinkles, hair growth and obesity have

in common? All three may involve the same gene, according to researchers at

Washington University School of Medicine in St. Louis.

The team discovered that mice with a mutation in the gene that produces a

protein already being investigated as a target for anti-obesity drugs fail

to develop wrinkles or normal hair growth.

The study is scheduled to appear the week of April 7 in the Online Early

Edition of the Proceedings of the National Academy of Sciences. H.

Miner, Ph.D, associate professor of medicine and of cell biology and

physiology, led the study; Casey L. Moulson, Ph.D, research associate in

medicine, is first author.

" This certainly was a surprise to us, " Miner says. " Obviously these are very

preliminary findings, but they may provide insight into a variety of

conditions. For example, if a drug could partially inhibit this protein, it

might be able to mimic some of the traits of these wrinkle-free mice. These

results also raise the possibility that anti-obesity drugs targeting this

protein may cause side effects elsewhere in the body. "

While developing genetically altered mice for a different purpose, the team

discovered that one strain of mice had perpetually open mouths and extremely

tight, thick skin. The animals resembled humans with a rare genetic disorder

called restrictive dermopathy. Like humans with the disease, the mice died

shortly after birth.

In addition, when skin samples from these mice were grafted onto healthy

animals, they did not develop nearly as much hair as skin grafts from normal

mice.

The team was even more surprised by the location of the genetic mutation in

these mice ­ it was in a gene that triggers production of a protein believed

to transport fatty acids. The gene already is considered a potential target

for anti-obesity drugs.

The protein, called fatty acid transport protein 4 (FATP4) is one of six

proteins of its kind identified in humans and one of five in mice. When

added to cells in a petri dish, these proteins change the way cells absorb

fatty acids. Since FATP4 is the only such protein found in the intestine, it

is thought to be important in processing fatty acids from the diet. But

there is little scientific evidence about the protein's role in living mice

and humans.

" No one even considered that this protein may be involved in skin

development, " Miner says. " In fact, of the 14 candidate genes we identified,

this was one of the last ones we examined because it seemed like such an

unlikely culprit. "

During development, the skin forms a barrier to keep water from evaporating

out of the body and to prevent harmful substances from entering. Mice with

the FATP4 mutation did not fully develop this skin barrier. Instead, they

had skin about three times as thick as that of normal mice. The team

concludes that abnormal skin thickness may be used to attempt to compensate

for the missing protective shield.

But the FATP4 mutation may play an even earlier role in development. The

skin's natural barrier cannot be made without lipids (a class of molecules

that includes fatty acids), but it does not begin to form until late in

embryonic development. In contrast, Miner and his colleagues found

significant wrinkle and hair-growth deficiencies much earlier in

development.

" These findings demonstrate a critical and unexpected role for FATP4 and

suggest that lipids may have a role in earlier developmental stages of skin

formation than previously thought, " Miner explains. " In collaboration with

others at the School of Medicine who already have been investigating FATP4

and its relatives, we plan to further examine the role of these proteins in

important developmental pathways. "

Miner and his team have applied for a patent for the use of inhibitors of

FATP4 to prevent wrinkling or hair growth and plan to continue investigating

the protein's role in skin development and in the intestine.

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Moulson CL, DR, Lugus JJ, Schaffer JE, Lind AC, Miner JH. Cloning of

wrinkle free, a previously uncharacterized mouse mutation reveals crucial

roles for fatty acid transport protein 4 in skin and hair development.

Proceedings of the National Academy of Sciences, April 2003.

Funding from the National Institutes of Health supported this research.

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Note: This story has been adapted from a news release issued for journalists

and other members of the public. If you wish to quote from any part of this

story, please credit Washington University School Of Medicine as the

original source.