Scientists have long speculated obesity was a complicated polygenicdisease and recent findings by two research groups demonstrate thedifficulties in unraveling the genetic components of the disorder.

In one study, researchers from Jefferson Medical College, inPhiladelphia, described how the obesity gene _ identified last yearby scientists at Rockefeller University, in New York, _ functions inhumans.

The Jefferson team determined the gene, which produces an appetitesuppressant hormone that tells the brain it's time to stop eating, is notdefective in obese people. The problem, the researchers discovered,is the brain apparently is not getting the message. The study appearsin the June issue of Journal of Clinical Investigation.

Jose Caro, chairman of Jefferson's department of medicine and leadauthor of the journal article, said the "obesity" gene is wronglynamed.

"It's a lean gene," Caro told BioWorld Today, "and it's doing theright job. The defect appears to be in the brain. The day we find thatdefect, it will be the obesity gene."

The Rockefeller University researchers, led by Jeffrey Friedman, firstdiscovered the gene in mice. They found it was inactive incongenitally obese mice, indicating the gene was involved in weightcontrol. Friedman's team also located the corresponding gene inhumans. (See BioWorld Today, Dec. 1, 1994, p. 1.)

Caro's group, which then cloned and sequenced the mouse obesitygene in humans, found it was the same in obese and lean people. Thepublished study included data from 16 people, but Caro said his teamhas compared the genes in 100 subjects with the same results.

Brain Doesn't Get Message

"We found in humans we have a perfectly functioning gene," Carosaid. "The fat tissue is sending the appetite suppressant signal to thebrain. Despite that the person keeps eating. There must be resistanceto the signal."

Another research team at the Jackson Laboratory in Maine hasdiscovered a different gene in mice that also may be related toobesity as well as diabetes. The findings appeared in the June issue ofNature Genetics.

The Jackson Laboratory researchers said they found a link betweenmice that get fat as they get older and a defect in a gene that producesinsulin. The scientists called their discovery the "fat" gene.

Jurgen Naggert, one of the Jackson Laboratory team scientists, saidthe defective gene prevents the mouse from producing an enzymeknown as carboxypeptidase E, which is involved in making insulin aswell as other hormones.

The mice produce inactive insulin, he said, and to compensate theytry to produce more insulin. The overcompensation process maycontribute to the obesity, Naggert said. But a more likely scenario, headded, is that the defective gene results in a failure to produceanother hormone used by the brain to control weight.

The hormone, Naggert said, may be involved in enabling the brain tomaintain a balance between energy intake and activity and heatproduction to get rid of those calories.

No Corelation In Obesity, Fat Genes

Unlike the obesity gene, no corresponding human "fat" gene has yetbeen found and no correlation between the two genes in mice hasbeen discovered. The "obesity" and "fat" genes are located ondifferent chromosomes.

Naggert said research is just starting to unravel the genetic links toobesity and "right now things are still unconnected."

One out of three adults in the U.S. is considered clinically obese, thatis 20 percent overweight. Researchers have speculated genes areresponsible for 60 percent to 90 percent of the variability in people'sweight.

In March, Amgen Inc., of Thousand Oaks, Calif., paid RockefellerUniversity $20 million up-front for licensing rights to the "obesity"gene discovered by Friedman's group. The company also agreed tomake milestone payments to the university totaling as much $70million in development of products from the gene.

Caro said the findings of his Jefferson Medical College team suggesttwo courses of research involving the "obesity" gene: one is to learnhow to produce more appetite suppressant hormone and the other isto determine why the brain is not reading the signal to cease eating.Caro said his researchers are continuing work in the latter area.

Treating obese people with appetite suppressant hormone, he said,would have the effect of blasting the signal so loudly that the braincan't ignore it. Caro likened the situation to Type II diabetes patients,who produce their own insulin, but whose bodies' don't respond tothe hormone. Giving them more insulin, he said, still is the besttherapy. n

-- Charles Craig

(c) 1997 American Health Consultants. All rights reserved.

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