From pleasingly plump to pathologically obese,overweight people hear the same advice, again and again,from friends, relatives and physicians: "Diet and exercise,exercise and diet."

Few of them really get the message. The fact that one-third of adult Americans are 20 percent or more abovetheir appropriate body weight makes that clear. Ironically,a hormone inside their own bodies is signaling a similarmessage, but it isn't getting through to the obese personeither.

That hormone, now known as leptin, is a proteinexpressed by the ob obesity gene. Molecular geneticistJeffrey Friedman and his colleagues at the RockefellerUniversity in New York, discovered that ob gene in micelate last year. (See BioWorld Today, Dec. 1, 1994, p. 1.)They found it in a strain of mice born naturally obese, andlacking a functional copy of ob.

Since that discovery, research in humans has uncoveredan apparent paradox: Leptin, a metabolic monitor of foodintake and energy need, supposedly turns the brain'sappetite message off when it senses that the body had hadenough to eat. Yet, recent studies show that most obesehumans have no lack of leptin; on the contrary, they makehigh levels of the protein.

This suggested a similarity to type II (adult onset)diabetes, whose sufferers produce a great deal of insulin,but can't respond to it metabolically. Their bodies areinsulin-resistant.

Obesity researchers wondered whether overweightindividuals making plenty of leptin could be resistant tothat hormone's `Time-to-stop-eating' message. If so,might giving such patients even more leptin correct theircondition, just as type II diabetics receive excess doses ofinsulin, to outweigh their bodies' resistance.

Leptin's Receptor Holds The Key

To molecular biologist Louis Tartaglia, who heads theobesity drug program at Millennium PharmaceuticalsInc., of Cambridge, Mass., the leptin paradox suggestedhunting down the protein's receptor. "By stimulating thereceptor," Tartaglia explained, "you would send themessage that leptin sends, which is: `Stop eating so much,and lose weight.'" He added, "Leptin is more than asignal just to eat less. It also has effects on metabolic rate,as well as the balance between adipose fat and lean bodymass."

Today's journal Cell carries a report by Tartaglia and hisco-authors titled "Identification and expression cloning ofa leptin receptor, OB-R." This discovery is a jointsuccess, he pointed out to BioWorld Today, betweenMillennium and its scientific partner, Hoffmann-LaRoche Ltd., mainly with its Research Center in Ghent,Belgium.

"It's been quite a close collaboration," he said. "Both ofus were hunting for a region in the brain that boundleptin, and in that we were both successful.

"Leptin itself," Tartaglia explained, "is a medium-sizeprotein produced by adipose tissue, and secreted into theblood, presumably as a factor that is basically telling youhow big your fat pads are."

It was in the brain that the Millennium and Rocheresearchers located the receptor that binds leptin.Specifically, they found it in the choroid plexus. Thesefringes of delicate capillaries line the cerebral ventricles_ channels that bathe the brain in cerebrospinal fluid.

The team made a cDNA expression library from thatmurine tissue source.

"There we could see leptin binding," Tartaglia continued,"which suggested that there were receptors there, and thatthere would also be messenger RNA encoding theseleptin receptors in that brain tissue." Presumably, theseOB-R receptors clue the brain into recognizing leptin'ssignal to stop eating.

In actually identifying the OB receptor, the Millenniumgroup turned to expression cloning, a biochemical ratherthan a genetic approach. "It means expressing in a cellline mRNAs produced in a given tissue," Tartagliaexplained. "Then we asked the question: Do any of theproteins encoded by these genes show the leptin-bindingproperty we want?"

To detect this binding, the team tagged their leptinmolecules not with conventional radioisotopes but byfusing them to molecules of alkaline phosphatase, "whichcan be detected quite readily." He describes such use ofthese fusion proteins, as "innovative," and is nowemploying the receptor itself "to identify the moleculesinside the cell that this leptin receptor interacts with andworks through."

Aim: To Treat Obesity By Mouth, Not Needle

He pointed out that "the molecules that mediate the signaloff of the leptin receptor could be pharmaceutical targetsfor orally available drugs, either to stimulate the receptordirectly _ if we're concentrating on obesity _ or thereverse, inhibiting leptin binding to treat cancer cachexia[tissue wasting] or anorexia."

Leptin-based obesity pharmaceuticals, under developmentelsewhere, must be taken by injection rather than in pillform.

High on Tartaglia's agenda is determining whether his obreceptor gene is actually encoded by the mouse db[diabetes] gene. Both lie within the same small region ofmouse chromosome 4.

"Traditionally," he observed, "how you finally resolvethe functional importance of a gene like our receptor geneis a long procedure. It involves making a knockout mousein which you ablate the gene, and then be certain you getthe phenotype you expect."

He continued: "If in fact this is db, the experiment hasalready been done for us by nature, as we know that thedb mouse has a phenotype identical to the ob mouse. Ifwe can show that the gene encoding our OB receptor isthe same as db, then we'll have demonstrated that withoutthis receptor, leptin can do nothing."

And with it, he implied, an obesity pill is somewheredown the road.

Stampeding down that road, Tartaglia concluded, "isquite an intense and heated race among academia, biotechand pharmaceutical companies." n

-- David N. Leff Science Editor

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