The Obesity Gene

Actually isolating a gene that causes obesity would complete our story. When it was announced that such a gene was found in mice it made big headlines. This gene is called the obese gene or the ob gene. In order to find a gene like this it helps to have inbred mice that are almost identical in every way except that some are obese and some aren't. Scientists have had such a breed of mice. It has been long known that the ob gene is recessive in these mice. By cross breeding hundreds of these mice and watching markers on their chromosomes, they were able to narrow the search of the culprit obesity gene down to chromosome 6 and then to the specific area and spot. It actually turned out to be a non-obesity gene. In other words, the gene was either missing or flawed in the obese mice but not in the normal sized mice.

Once you have the DNA sequence, it's a straightforward process to look for the RNA and the protein that the gene produces. You can see which body tissues are the ones that make the RNA and the protein. You can look for it in other animals. Finally, the protein in hand, we can begin to figure out what it does to the body by making it or extracting it and giving it to mice or people. Leptin is the name of the protein encoded by the ob gene.

Friedman and Zhang and coworkers, in the article in Nature where they announced the discovery of the ob gene, had already done some of this follow-up work. They showed that the gene is present in cats and rats and pigs and in every vertebrate animal they checked, including humans. When genes are conserved like that across many species, it usually means that it has a basic and important function. They checked different tissues and found it expressed only in adipose tissue of mice and humans. In the obese mice the RNA was either not present or there was an excess of flawed RNA that would indicate that the feedback loop was not working.

The site and mechanism of action of leptin is yet to be discovered. Friedman and Zhang, the original discoverers, surmised that it probably sends signals to the brain that describe the size of the fat depot. Since obese people have high levels of leptin that may mean that their brains are resistant to its effects.

The ob gene could have been the Holy Grail of obesity treatment. It could have greatly simplified everything. Maybe we could stop treating obese people as if they have emotional problems or blaming them for watching too much TV. But if you have the sinking suspicion that it's not that simple, you're right.

Considine and all, looked for the leptin deficiency in obese humans. He could not find it in the 10 individuals he checked. More recently humans with this ob gene defect have been found but they represent a tiny minority of the obese population.

So what does this gene do in humans? Stay tuned.