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MORE GENETIC PIECES IN THE OBESITY PUZZLE

By Sean Henahan, Access Excellence


BAR HARBOR, MAINE- The recent discovery of another gene associated with obesity could help explain the physiological mechanisms of overeating, obesity and certain types of diabetes, report researchers.

Late last year researchers identified the 'obese gene' or 'ob'. The 'ob' gene appears to play a role in the signaling pathway from adipose tissue that in turn regulates the amount of stored body fat. Mutation of this single gene is associated with development of profound obesity and non-insulin dependent diabetes in mice. The syndrome in mice closely parallels morbid obesity in humans,

The researchers also cloned and sequenced the human homologue of the 'ob' gene. The human homologue matches 84% of the murine nucleotide sequence. Moreover, further investigations revealed that the ob gene appears to be conserved in most if not all vertebrate DNA, suggesting a long heritage.

Now, researchers at Jackson Laboratories, Bar Harbor, Maine, have discovered another gene in mice that affects both obesity and diabetes, dubbed 'fat' , on Chromosome 8. Mutations in the 'fat' gene appear to affect metabolism rather than regulating appetite. Single mutations in the gene prevent mice from synthesizing carboxypeptidase E, a key enzyme involved in processing insulin. Carboxypeptidase E (CPE) helps convert the insulin precursor proinsulin into insulin.

Contrary to expectations, the mice with the mutated 'fat' gene, although obese, did not have insulin resistance, although they did have elevated blood sugar levels. Insulin resistance is seen in humans with adult-onset type II diabetes, the type often seen in obese people. Rather, it appeared the poor biologic function of the mice's own insulin was due to the build-up and release of the less-active precursor, proinsulin.

"The fat mutation represents the first demonstration of an obesity-diabetes syndrome elicited by a genetic defect in a prohormone processing pathway. What we set out to do was to find an obesity mutation, but what we ended up finding was a generalized defect in hormone processing. At this point, we don't really know what the cause for the obesity is. It could be a defect in the insulin processing, but it could equally as well be a defect in the processing of a variety of other hormones in the brain. And that is the next thing to find out.

"The problem we now have is to identify how many of these hormones have to be processed normally by CPE if obesity is to be avoided. I think that the significance of our discovery is that is gives us a way to investigate this whole pathway and what parts of the pathway are involved in obesity," said Dr. Jurgen Naggert of the Jackson Laboratory.

The recent discoveries of 'ob' and 'fat' appear to support the hypothesis that obesity is a heritable trait influenced by several genes. Single locus mutations associated with obesity are important they provide clues about pathways involved in fat depot size in mammals. The current research is likely to lead to the identification of other genes involved in the control of fat deposition via interaction with obesity gene products, noted Peter Keightley, Institute of Cell, Animal and Population Biology, University of Edinburgh.

Another group of researchers reported further data regarding the 'ob' gene. Dr. Jose Caro, chairman of the department of medicine, Jefferson Medical College in Philadelphia, and colleagues have completed a study suggesting that in overweight people, the brain ignores appetite suppression messages sent by the 'ob' gene. This contrasts with earlier 'ob' gene research suggesting a mutation in the gene as the root of obesity.

These findings are likely to fuel the ongoing debate on the physiological mechanisms of appetite and satiety. While there is a consensus that the hypothalamus plays role in energy balance (i.e. food intake versus energy output) researchers disagree on the nature of the feedback loop responsible for regulation of this system.

Proponents of the lipostasis theory maintain that the amount of body fat is regulated by the central nervous system via a product of fat metabolism in plasma. Supporters of the glucostasis theory believe that plasma glucose level is the key to energy balance regulation. A third group advances the concept that thermal regulation of food intake interacts with the central nervous system center responsible for controlling appetite and satiety.

Identification of the 'ob' and 'fat' genes will open many new avenues of research into the regulatory mechanism of adiposity and body weight. In addition to increasing current understanding of the pathogenesis of obesity, this research could lead to the development of bioengineered treatments for nutritional and metabolic disorders.

For more information on 'fat' see Nature Genetics, 6/95, v.10, Naggert et al., pp 135-141; and Keightley, pp125-126. Dr. Caro's study appeared in the Journal of Clinical Investigation, 6/95. Also see Nature, 12/1/94, v.372, J. Friedman et al., for info. on the 'ob' gene discovery.



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