"An estimated $33 billion a year are spent on weight-loss measuresthat are largely futile." Canadian endocrinologist Bradford Hamilton,whose research focus is obesity, wrote these words to preface aneditorial titled, "A new role for a fat actor," in the March 1996 issueof Nature Medicine.

That "fat actor" is a recently discovered protein named leptin, whichapparently acts as an "adipostat," controlling the balance betweenfood intake and adipose tissue. (See BioWorld Today, Feb. 12, 1996,p. 1.)

Leptin's new role involves honchoing mammalian fertility.Hamilton's commentary reviewed a paper in the March NatureGenetics, which reported: "Correction of the sterility defect inhomozygous obese female mice by treatment with the humanrecombinant leptin." (Hamilton's research lab is at the SunnybrookHealth Science Center in North York, Ontario.)

Its senior author is molecular biologist Farid Chehab, who runs anobesity lab at the University of California's department of laboratorymedicine in San Francisco.

"Genetically obese mice are huge," Chehab told BioWorld Today.They get up to 90 or 100 grams weight, at least three times heavierthan normal mice. And it all runs to body fat."

Such hyper-stout females, of the ob/ob obesity mutant strain, have"absolutely no libido," Chehab observed. "They have difficultymating, can't get pregnant, and remain prepubertal indefinitely.Although these animals have scanty levels of reproductive hormonesin their own circulation, their ovaries, when transplanted into normalfemales, function normally."

Chehab set up a multi-stage breeding and mating experiment to teaseout the respective roles of corpulence and leptin in this sterilitysyndrome.

For starters, he and his co-authors gave recombinant human leptin toseven ob/ob females for 30 to 42 days. Their body weight dropped by48 percent. Six of the newly slenderized mice were mated, and dulydelivered litters of newborn pups after the usual 20 days of murinegestation.

These same new mothers continued receiving leptin injections, andproduced a second litter from a second mating.

Leptin, Not Weight Loss Per Se, Restored Fertility

Meanwhile, a control cohort of seven ob/ob mice got dummyinjections of saline. They put on another 13 percent of weight, andremained infertile. A third batch of seven received no injections, butreceived a starvation diet. They lost 35 percent of their avoirdupois,but didn't get pregnant either. "This shows," Chehab said, "thatweight loss was not responsible for return to a fertile state."

He observed that, "Many, but not all, morbidly obese humans, men aswell as women, are also infertile. However, the story in such obesewomen is different than in our obese mice. These ob/ob animals don'thave leptin in their blood, because their leptin gene is mutated. Obesehumans, on the other hand, have excess leptin in their circulation."

From this, the California scientist suggested that "In humans theinfertility of obesity appears to be a defect at the level of the leptinreceptor, or beyond."

He went on to point out that extremes of skinniness as well as fatnessbring on human sterility. "Women who get very thin," Chehabexplained, "as by jogging, lose a lot of their fat, and they stopmenstruating. These women may have a parallel with the leptin story_ as far as the protein itself is concerned, not its receptor.

"My theory is that they are depleting the level of leptin, maybe notcompletely, but to a certain threshold. They stop menstruatingbecause they stop ovulating. They can have sex but they can'treproduce. When they stop running and regain more fat, they startmenstruating again."

To unravel the leptin connection between fat and fertility, Chehabstarts in the brain, with the hypothalamus.

He speculated that leptin, already known to act on the hypothalamus,"can stimulate it to release gonadotropic releasing hormone (GRH)into the pituitary gland just below it. This in turn," he went on, "sendsfollicle-stimulating hormone (FSH) and luteinizing hormone (LH) tothe ovaries, and stimulates them to make steroids."

Chehab observed: "We know that these sterile, obese mice havenormal content of GRH, FSH and LH in their pituitaries, but lowlevels in their circulation. So there seems to be a problem in secretingthese hormones from the hypothalamus, for example, to the pituitary,and on to the target organs _ ovaries, testes, breasts."

Fertility Drug In Leptin's Future? Stay Tuned

Given the action of leptin in slimming and trimming mice down fromsterility to fertility, and the parallels to the human condition, mightthe protein or its derivatives provide drugs to help infertile coupleshave children?

"That's exactly what the media want to hear," Chehab said. "But westill have some hormones to do. We first have to identify the pathwayin which leptin works, as far as drugs are concerned. Once we'vefigured that one out in mice _ which shouldn't be extremely difficult_ then we can look at whether there are deficiencies in this pathwayin humans."

He continued: "It's very clear that there is no genetic defect at thelevel of the leptin protein in humans. Now we're trying to see ifthere's a problem in the regulation of the gene, why leptin levels areso different.

"What the biotech industry wants to hear," he said, "is whether therereally is a drug, whether it can be marketed, whether there can bemoney in this. I think there is. We just have to do a bit morehomework. All I say is, `Stay tuned.'" n

-- David N. Leff Science Editor

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