The leptin hormone is no longer alone on the list of proteins that appear to play a key role in regulating weight gain. One of its partners is a protein called agouti, previously known for its role in regulating coat color in mammals (see ScienceNOW, 3 January; and Science, 7 February, p. 751*). Now, a new mouse model, described in the current issue of the Proceedings of the National Academy of Sciences, may help researchers understand agouti's role in regulating body weight--information that may lead to new drugs for treating obesity.
Previous evidence implicating agouti in weight control comes from a naturally occurring mutant mouse strain that produces agouti in all its tissues, with the result that it not only becomes obese but also develops diabetes as a result of insulin resistance. Normal mice only make the protein in hair cells, however. In contrast, humans, even those of normal weight, express the gene in their fat cells, where its function is currently unknown.
To get a better idea of what agouti does in fat cells, Rick Woychik and his colleagues at Oak Ridge National Laboratory in Tennessee first attached the agouti gene to a regulatory sequence that causes the gene to be turned on in adipose tissue. They then transferred this hybrid gene into normal mouse embryos, which then grow up to make the protein in their fat cells. Like normal humans, these transgenic mice did not become obese. But they did when the scientists gave them injections of insulin, a hormone that helps cells use simple sugars. Animals that received daily insulin injections for 1 week gained 1.7 times as much weight as nontransgenic animals given the same amount of food.
"This suggests that the agouti gene plays some role in adipose tissue function and that the [protein] acts synergistically with insulin to promote weight gain," Woychik says. Indeed, he suggests that in the naturally occurring obese agouti mutants, the abnormal production of the protein may in fact stimulate excess insulin production by the pancreas, which might then not only help cause the animals' weight gain, but also lead to their eventual insulin resistance and diabetes.
Exactly how agouti and insulin interact on adipose tissue "is the big question," says George Wolff, a geneticist at the National Center for Toxicological Research in Jefferson, Arkansas. And finding the answer, Wolff adds, is likely to be difficult, because the system involved in weight regulation is "very complicated and complex." Nevertheless, having this new molecularly engineered mouse should help scientists trace out the intricate pathways of fat regulation, says Woychik. Once those pathways are known, he adds, it may be possible to develop drugs that stimulate or block them to trigger weight gain or loss.
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