A triad of papers in Friday's issue of Science drops thesecond shoe on the obesity (ob) gene discovered last yearat Rockefeller University.

Molecular geneticist Jeffrey Friedman, of Rockefeller'sHoward Hughes Medical Institute, who located that obesegene in mice, weighs in this time with the logical nextstep _ a report titled: "Weight-reducing effects of theplasma protein encoded by the obese gene." (SeeBioWorld Today, Dec. 1, 1994, p. 1.)

The two other Science articles, whose authorsindependently cloned the same gene product, are fromHoffmann-La Roche Inc., Nutley, N.J., and Amgen Inc.,Thousand Oaks, Calif.

Release of the recombinant protein news came almostsimultaneously with an announcement from MillenniumPharmaceuticals Inc., which on Wednesday said that theyhad found and cloned the tub gene. (See BioWorldToday's Special News Bulletin, July 26, for more details.)

"It's just an active area of research," Friedman toldBioWorld Today, "and a lot of people were doing thesame experiments at the same time." Each of the threelaboratories cloned its own protein, he added, after hispaper in Nature, dated Dec. 1, 1994, published 2,500 basepairs of the murine gene's entire sequence.

The human ob gene, Friedman confided, has just beentracked to chromosome 7, "by another laboratory."

Body fat is the sole known tissue in the body thatsynthesizes the 16-kilodalton OB protein, he observed,"but that doesn't exclude formally the possibility that itcould be made elsewhere. That's why it's going to beimportant to find the protein's receptor." Logically, thiswill be the third shoe to drop, after the gene and itsprotein.

Friedman made the point that, "Over time, as more andmore genes are identified, a fuller picture will emerge asto the nature of the mechanism that regulates bodyweight. This is just one of what we believe ultimately willbe many important proteins in that process."

After testing OB's fat-shedding effects in mice bornobese, Friedman and his co-authors named their hormone"leptin," from the Greek word "leptos," meaning "thin."Healthy, non-obese humans, they reported, have leptin intheir blood.

The researchers found that obese mice, whose genomeharbors a defective ob gene, do not synthesize leptin.Conversely, another kind of obese mouse, with adefective gene called diabetes (db), make 10 times moreof the hormone than normal mice, Presumably, db micehave a defective leptin receptor.

The team injected the hormone daily into the peritoneumsof 10 ob, 10 db and 10 normal rodents. Control animalsgot saline or no treatment.

"The effect of the laboratory-derived leptin on foodintake and body weight in mice is dramatic," said co-author Stephen Burley, who cloned the recombinanthormone in E. coli hosts.

After two weeks on leptin, the ob animals lost 30 percentof their body weight _ all of it in fat. They ended upwith 9.1 grams of body fat, compared with 38.30 gramsin their untreated ob controls. A normal, healthy adultmouse carries only two to five grams of adipose tissue.Leptin trimmed away almost all that fat, and droppedtheir weight about 12 percent.

These weight decreases resulted directly from a sharpdecline in the animals' food intake, due in turn to loss ofappetite. They occurred from both murine and humanleptin treatment.

"That fact," Friedman observed, "raises the possibilitythat giving leptin to people might have similar effects.However, we must proceed cautiously to prove that theprotein treatment is safe in animals."

Although Amgen holds an exclusive license toFriedman's leptin ob gene (see BioWorld Today SpecialBulletin, July 26), the company made its ownrecombinant protein for experiments it reported toScience as: "Effects of the obese gene product on bodyweight regulation in ob/ob mice."

Clinical Trials Possible Next Year

Its senior author, neuroendocrinologist Frank Collins, isAmgen's director of neuroscience. He told BioWorld:"Certainly we are encouraged by the basic observationthat the protein causes a substantial reduction in bodyweight and body fat, both in obese and normals." Headded, "We are encouraged by that to think of possibleclinical applications, but it's important to remember thatthese are early studies in animals."

But Collins allowed, "We are moving forward, and as ourprogram progresses it's possible that we may be able toengage in the first clinical studies as early as next year."

One "very interesting thing" that emerged from Amgen'smouse studies, he pointed out, "is the fact that the OBprotein had effects in the ob mice that were moreextensive than just those on appetite. It made theiractivity level normal."

Obese mice are naturally sluggish, and have reducedmetabolism and body temperature. "The OB protein,"Collins said, "brought all these to normal levels."

Amgen has "active programs to investigate the best wayof delivering the protein to humans," Collins said,whether by injection, by mouth, by inhalation or otherroutes. "It may be chronic therapy [like insulin] but it'spremature to speculate about that right now."

Hoffmann-La Roche, the third main player in the obesity-gene game, tested its OB protein by direct injection intothe brains of mice, as well as systemically. Its Sciencepaper bears the title: "Recombinant mouse OB protein;evidence for a peripheral signal linking adiposity andcentral neural networks."

Neurophysiologist Arthur Campfield, that paper's firstauthor, is a research leader in Roche's department ofmetabolic diseases. He told BioWorld: "Amgen is bettingon a single molecule, which will be therapeuticallyuseful. We believe obesity is a multifactorial disease.We're interested in the pathway that integrates multiplesignals."

He added, "So ours is a very different approach, and wewish Amgen well. We'll be very interested to see theirresults when they give people OB protein. To see whatsort of effects they get, and more importantly, how longthey last, because I would speculate that there could besome counter-regulatory mechanism that would comeinto play." n

-- David N. Leff Science Editor

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