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OB GENE PRODUCT: WEIGHT LOSS WONDER?

By Sean Henahan, Access Excellence


WASHINGTON, D.C. A protein product of the recently identified obesity gene (ob) appears to cause weight loss in experimental animals, reported researchers in a series of news studies.

The reports come only months after researchers reported the identification, cloning and sequencing of the ob gene, the culmination of eight years of work. The initial research showed that mice with mutations in the ob gene do not make the ob gene product, now called leptin (from the Greek leptos, meaning thin), believed essential for weight maintenance.

Three separate teams reported that injections of leptin caused mice to lose weight and keep the weight off. The mice were a special breed of genetically obese animal known as ob/ob mice because they have two mutant copies of the ob gene. The leptin was expressed in E. Coli from a PET 15b plasmid and was then purified and renatured.

The obese mice dropped 40% of their body weight after on month of treatment with the protein. The leptin injections also appeared to improve symptoms of diabetes in the mice. Non-obese mice also lost weight when given the protein.

"I'm really impressed. The level at which body weight is defended is reduced by this stuff," obesity researcher Richard Atkinson, University of Wisconsin, told Science magazine.

Another gene identified in a different strain of obese mice called db (for diabetes) has also been identified. Leptin injections had no effect on this kind of mice. This supports a previous hypothesis that db mice had an impaired receptor for leptin.

Earlier research suggested that ob gene regulates energy balance in the mouse. The gene appears to play a role in the signaling pathway from adipose tissue that in turn regulates the amount of stored body fat. The ob gene encodes a protein secreted by fat cell and associated with satiety, the signal to stop eating. Mutations of this gene prevent translation and expression of the gene product. Lacking this satiety factor, the mice become obese.

The current research suggest the gene product both reduces the mouse's appetite and increases its metabolism. "The new findings indicate that when ob is defective, leptin is not made and does not transmit the signal to stop eating," said Jeffrey Halaas, a research fellow at Rockefellar University and lead author of one of the studies.

It remains to be seen whether the compound causes similar effects on human metabolism. A human homologue of the gene has also been cloned. The human homologue matches 84% of the murine nucleotide sequence. Indeed, obese mice injected with human leptin also lost weight. 'The fact that human leptin reduces weight in the mice raises the possibility that giving leptin to people might have similar effects. However, we must proceed cautiously to prove that the protein treatment is safe in animals. Studies of humans cannot begin until the protein has been confirmed to be without unwanted side effects,' said Jeffrey Friedman, M.D., Ph.D., of Rockefellar university.

If similar effects are seen in humans, the protein could form the basis for a whole new way of treating obesity. A biotech company has already paid $20 million for rights to develop potential drugs from the ob gene product.

"While diet and exercise are presently the cornerstone of weight control, this new molecular approach to understanding the regulation of body weight is one of the best examples of real progress in biomedical research," noted Philip Gorden, M.D., director of the National Institute of Diabetes, Digestive and Kidney Diseases.

These current findings contribute much to the study of the physiological mechanisms of appetite and satiety. In particular, the discovery of the ob gene has added support to the theory of lipostasis wherein the amount of body fat is regulated by the central nervous system via a product of fat metabolism in plasma.

The identification of the ob gene suggested a possible source for generation of a blood borne regulatory factor. It is possible that the level of expression of this gene determines the size of the body's fat stores. Researchers now hypothesize that an increase in the level of the ob signal following a session of overeating may act directly or indirectly on the central nervous system to maintain body fat at the post-binge level.

The next stage will be to identify the location of the leptin receptor. Preliminary research suggests the receptor may be found in the brain. The three latest studies on the ob gene appeared in Science, 7/28/95, Vol. 269, in articles by Halaas et al., pp 543-546; Campfield et al., 546-548; and Pelleymounter et al, 540-543. The original report on the ob gene localization appeared in Nature, 12/1/94, v.372, Freidman et al.


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