Mice provide clues about obesity, wrinkles, hair growth

What do wrinkles, hair growth and obesity have in common? All three may involve the same gene, according to School of Medicine researchers.

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 appeared in the April 7 issue of the online early edition of the Proceedings of the National Academy of Sciences.

Jeffrey H. Miner

Jeffrey 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 said. “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 is already 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.

Because 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 said. “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 concluded 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 said. “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.