"If rats were the main staple of the American diet," said physiologistand diabetologist Roger Unger, "we would be able very easily toproduce fat-free rats, and open butcher shops in which we could sellfat-free meat."
Unger, who directs the Gifford Laboratories for Diabetes Research atthe University of Texas Southwestern Medical Center in Dallas, wasonly half-kidding.
He is co-senior-author of an article in the current Proceedings of theNational Academy of Sciences (PNAS) dated Dec. 10, 1996, whichdocuments his tongue-in-cheek vision. Its title: "Disappearance ofbody fat in normal rats induced by adenovirus-mediated leptin genetherapy."
Leptin, of course, is the putative anti-obesity peptide that up to adozen biotech companies are scrambling to bring to market. (SeeBioWorld Today, Aug. 16, 1996, p. 1.)
But, "As far as treating human obesity," Unger told BioWorld Today,"this PNAS paper has no implications whatsoever, for severalreasons. First of all, it involves an adenovirus infection. Second, itinvolves normal animals, not obese ones. The only immediatepractical implications that I could see," Unger added, "would beapplying our fat-depleting results to poultry, or even large animals,because it would probably be more feasible than giving huge amountsof recombinant leptin by injection."
He and his co-authors "have not stressed this idea in our paper,"Unger continued, "but we've been thinking along these lines. So Ithink there's a possibility, and maybe we're going to be contacted bysome chicken manufacturer who buys this idea."
Their idea, in brief, is that leptin, besides abating appetite anddecreasing food intake and body weight, has other properties beyondsatiety, including ablation of body fat.
They injected their gene-therapy package of leptin cDNA wrapped inan adenoviral vector (AVV) into the tail veins of normal rats. Theleptin genes headed for the animals' liver, and started expressingtheir slim-quick diet peptide product. Ordinarily, the site of leptinproduction is adipose tissue.
These recipient rodents duly developed hyperleptinemia, droppedtheir food intake by 30 to 50 percent, and gained only 22 grams inbody weight during a 28-day experimental period. Meanwhile,control animals, which received either an irrelevant virus or none, puton 115 to 132 grams of avoirdupois.
Leptin's Other Metabolic Lives
What's more (or less?), the leptin-gene-expressing animals lost alltheir grossly identifiable adipose tissue _ became fat-free.
"What we wanted to find out" said the paper's co-senior author,biochemist and molecular biologist Christopher Newgard, "waswhether the increased leptin had any effect in addition to the fact thatfood intake was reduced." The group set up two matched sets ofpaired rats, one hyperleptinemic, the other normal, and fed thecontrol cohort exactly as much food as the high-leptin group hadingested spontaneously.
"Our paper shows," Newgard told BioWorld Today, "that thecontrols gained body weight much faster. But then," he continued,"the amazing thing is that the hyperleptinemic animals lost all theirfat, and those that were simply pair-fed did not. That's what providesus with the implication that leptin really has powerful metaboliceffects in addition to what it's doing to food intake."
People in a clinical trial of anti-obesity prescription drugs, such asfenfluramine and phentermine, lose weight, all right _ from five to22 pounds more than control patients on placebo or no drug. TheNational Task Force on the Prevention and Treatment of Obesityreleased this finding in today's issue of JAMA, Journal of theAmerican Medical Association.
Their report bears the title: Long-term pharmacotherapy in themanagement of obesity." And its downbeat bottom line is that "oncethe weight-loss drugs were stopped, patients regained lost weight."
Newgard and his team are "investigating such a rebound consequenceof removing leptin therapy, but we don't have the answer yet."
He is founding scientist of a four-year-old Dallas-basedbiotechnology company, BetaGene Inc. It is funded "through astrategic collaboration with a very private company, Gore HybridTechnology, a subsidiary of W. L. Gore & Associates."
While "interested in the impact of leptin on obesity and diabetes,"Newgard stated, "nothing about leptin is currently part of BetaGene'spurview or portfolio. A major focus for us," he went on, "is insulindelivery in Type I diabetes. A lot of our pending and issued patentspertain to insulin replacement; others to other peptides."
Leptin Shows That Slimming Helps Diabetes
Almost back-to-back with the Dallas paper in the current PNAS isanother research article, titled: "Correction of obesity and diabetes ingenetically obese mice by leptin gene therapy." Its senior author,pioneer gene researcher Savio Woo, is now director of the Institutefor Gene Therapy and Molecular Medicine at Mt. Sinai Hospital,New York.
While at Baylor College of Medicine, in Houston, until lastSeptember, Woo and his colleagues treated genetically obese anddiabetic ob/ob mice with AVV-delivered leptin genes. Not only didserum leptin levels rise to 70 times those of control animals, and theirfood intake and body weight drop "dramatically," but the treatmentnormalized the animals' serum insulin levels and glucose tolerance.
These results "provide confirming evidence that body weight controlmay be critical in the long-term management of non-insulin-dependent diabetes mellitus in obese patients," Woo's paperconcluded.
The adenovirus vectors reported by both the Dallas and Houstonresearchers yielded short-lived leptin synthesis at best.
"It's conceivable that in some future time," Unger predicted, "whengene transfer techniques are much more advanced than today, onecould take a fat person, over-express leptin for a brief period of time,get rid of their fat and send them home." But he hastened to add:"It's very unlikely for the foreseeable future that this would have anyimpact on the management of human obesity." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.