Stanford Report Online

Stanford Report, February 21, 2001
Protein’s effects combine to distort body weight regulation


It was 100 years ago that scientists first described an unusually fat yellow mouse. In 1992, when researchers revealed the molecular defect that caused these mice to swell to twice their normal size, it heralded a new era in body weight research. The discovery of the defective mouse gene agouti, which induces morbid obesity, was soon followed by the discovery of the fat-regulating gene leptin. But now, almost 10 years later, a pill to combat obesity remains tantalizingly beyond reach.

Gregory Barsh, MD, PhD, associate professor of pediatrics and of genetics at Stanford and a Howard Hughes Medical Institute investigator, has dedicated his research efforts to understanding how biological pathways that control eye, hair, and skin color can provide insight into human development and disease. He and his colleagues have found that the regulation of body weight becomes skewed when proteins that determine pigmentation ­ normally produced in skin cells ­ are erroneously expressed in the brain.

Barsh presented an overview of the latest research from his lab Monday in San Francisco during a symposium on obesity at the annual meeting of the American Association for the Advancement of Science.

Members of Barsh's lab ­ postdoctoral fellow Teresa Gunn, PhD, and graduate student Lin He ­ are studying a protein called attractin, which is produced naturally in humans and mice. Attractin partners with a hair-color protein called agouti and its presence is required for agouti to exert its effects. Agouti is normally made in skin cells ­ producing yellow mice. But defects in the agouti gene cause it to be abnormally made in the brain ­ producing fat mice. Barsh and his colleagues determined that defects in the attractin gene prohibit agouti from affecting coat color or body weight in this way. Without attractin, fat, yellow mice are instead black and svelte. "We understand now why mutations in attractin modify obesity," said Barsh. "Attractin is required for agouti to have its effects ­ whether it's expressed in the skin or the hypothalamus."

But Gunn and He have also discovered that attractin's role in weight regulation is more profound than it first appeared, extending beyond its relationship with agouti. The researchers have uncovered an agouti-independent effect on body weight they believe is related to attractin's normal role in the brain.

"Attractin is important for normal brain function," said Barsh. "Animals that have mutations in attractin develop a spongiform encephalopathy that looks very much like the spongiform encephalopathy that you see in prion-related diseases." Prion-related diseases include bovine spongiform encephalopathy (also known as mad cow disease) and Creutzfeldt-Jakob disease, a degenerative brain disease in humans.

Barsh said these mice exhibit subtle behavioral effects associated with the brain disorder ­ they are hyperactive and are afflicted with a subtle tremor. Their body weight decreases because they are exercising more without eating more food.

"We think that neurodegeneration caused by the spongiform encephalopathy causes increased energy expenditure and, in ways that we don't understand, prevents the animals from compensating. Normally animals would compensate [for increased exercise] by increasing their food intake but these animals don't."

Barsh's team is still puzzling over the obscure links between attractin's varied effects in the body, which culminate to distort weight regulation. "We think those two functions ­ attractin's normal function in the brain and its ability to serve as a receptor for agouti ­ are completely separate functions," he said.

Researchers in Barsh's lab will continue teasing apart the threads that interweave the stories of agouti, attractin and spongiform encephalopathy but one thing that is already clear to him is that attractin's multifarious functions make it an unlikely target for a human anti-obesity drug. "The attractin story is really interesting but it is much more important for neurodegeneration than it is for obesity," Barsh said.

Funding for the research is provided by the National Institutes of Health and the Howard Hughes Medical Institute.