A much-quoted (and somewhat pudgy) American humorist,Alexander Woollcott (1847-1943), once confessed: "All the things Ireally like to do are either immoral, illegal or fattening."

No one has, as yet, isolated a gene for legality or morality, buttoday's issue of Nature announced "Positional cloning of the mouseobese gene and its human homologue."

One-third of all adult Americans are more than 20 percentoverweight, (i.e., clinically obese) the paper states. This "importantpublic health problem," its authors emphasize, "is associated withtype II [non-insulin-dependent] diabetes, hypertension,hyperlipidemia, heart disease and certain cancers."

That explains why a grant from the National Institute of Diabetes andDigestive and Kidney Diseases helped fund the obese gene'sdiscovery, reported today. The six co-authors work at theRockefeller University in New York, and the Howard HughesMedical Institute in New York.

Obesity runs in families, geneticists point out. From 60 percent to 90percent of the variability in people's weight is due to their genes;diet, exercise and environmental factors account for the rest. Notingthat an individual's weight seldom changes drastically over a lifetimeof eating, scientists hypothesize a feedback system that maintainsbody weight at a precise "set point" of plus or minus 1 percent.

To lasso and brand the suspected but unknown obesity gene and itsfat-depositing mutations, the Rockefeller group employed the gamutof positional-cloning technology _ exon trapping, physical mappingwith polymorphism analysis, artificial yeast chromosomes andpolymerase chain reaction amplification, northern and southern blothybridization of DNA, cDNA cloning, data base protein searches,1,606 genotype meioses scored . . .

In cloning and sequencing the mouse ob gene (which encodes a 4.5-kilobase adipose-tissue RNA) and its human counterpart, they found84-percent homology between the Mus musculus and Homo sapienssequences. Their data "suggest that the ob gene product, which has apredicted length of 167 amino acids, may function as part of asignaling pathway from adipose tissue that acts to regulate the size ofthe body fat depot."

Brain's Appetite-Energy Balancing Act

The Nature paper's principal author, molecular geneticist JeffreyFriedman, pictures the putative ob protein "as part of an endocrinesignaling pathway from adipose tissue that signals the hypothalamusto regulate the size of the body fat depot." The hypothalamus,perched atop the pituitary gland, is the brain's command post forbalancing appetite and energy.

In one strain of congenitally obese mice, Friedman et al. found theob gene completely inactive, indicating that in normal animals, theob protein keeps weight under control. A second murine strain'smutant ob gene inactivated its encoded protein, which it keptexpressing 20 times normal in a vain effort to make it perform.

"It is still necessary," Friedman emphasized, "to show that theprotein does in fact function as a hormone that regulates the amountof fat stored in the body." Experiments now under way in theRockefeller molecular genetics lab, which he heads, aim to confirmthis supposition by showing that the ob protein circulates in theblood, and that injections of normal protein will reduce the weight ofthose mutantly obese mice.

If the human protein turns out to regulate obesity as the murine onedoes, Friedman suggests, it would be theoretically possible to treatobesity by injecting the human protein, much as insulin treatsdiabetes.

In furtherance of this rationale, his group has begun to study thegenetics of inhabitants of Kosrae, an island in the Western PacificMicronesian archipelago, in whom the incidence of obesity isextremely high.

Gene therapy to correct the mutational defect, antisense RNA toblock mutated protein production and drugs to stimulate or inhibitob's signaling, are also under longer-range consideration.

Siamese-Twinned Mice Support ob Gene Function

Human physiologist Timothy Rink, president and chief technicalofficer of Amylin Pharmaceuticals Inc., in San Diego, wrote aneditorial titled "In search of a satiety factor" accompanying theNature paper. "It will not have escaped the notice of the authors orreaders," it concluded, "that cloning the ob gene may provide newand rational approaches to the therapy of obesity."

In his commentary, Rink described parabiotic experiments with miceto adduce the existence and function of the obesity gene and itsproduct. (Parabiosis involves surgically uniting the circulatorysystems of two organisms.)

* Joining two normal mice and overfeeding one of them "reducesfood intake and induces weight loss in the partner," suggestingtransfer of a circulating hormone.

* Lesioning the hypothalamus causes obesity in one parabioticmouse, but depressed food intake and weight loss in its intactpartner.

* Surgically joining an obese animal that carries a double dose(homozygous) of the mutated ob gene (ob/ob) causes similarsymptoms in its Siamese-twin fellow.

"Some cases of morbid obesity in humans," Rink commented, mayreflect a homozygous condition analogous to the ob/ob mouse. Withthe availability of Friedman's data, investigations of such casesshould be relatively straightforward."

He told BioWorld Today, "This is a pretty major discovery."

The Amylin executive's editorial also observed that dieting toachieve slimming "is likely to be only temporarily successfulbecause weight loss will reduce the production of the satiety factor,and there will be an enduring drive to increase food intake andreduce energy use until weight again stabilizes at the original obeselevel, with appropriate production of ob protein."

If the gene's putative product actually acts in vivo as a long-termsatiety hormone, Rink wrote, then "excess ob protein should inducestarvation in the face of abundant food _ truly nature's slimmingremedy." n

-- David N. Leff Science Editor

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