Sci. Aging Knowl. Environ., 30 June 2004
Protein might block body's response to fat-reducing hormone
As the brain decides how much food we should eat and how much energy we should use, it listens to molecules exuded by fat. But this communication breaks down in obesity. A new study reveals a possible reason why the brain pays less attention to a weight-regulating hormone. The results might help researchers design drugs to slim down the world's increasingly rotund residents.
Fat cells ooze a hormone called leptin that achieves what dodgy diet pills only promise. It restrains appetite and hikes energy use. When scientists uncovered leptin's role, they conjectured that a scarcity of the molecule might spur obesity. Instead, most obese people pump out excess leptin, but their bodies ignore it. Designing drugs to reverse this leptin resistance might help overweight folks slim down, but scientists don't understand what causes the problem. Leptin resembles immune molecules called cytokines, which another protein, Socs3, inhibits. Endocrinologist Jeffrey Flier of Beth Israel Deaconess Medical Center in Boston and colleagues wondered whether Socs3 also suppresses leptin and promotes resistance to the hormone.
Mice lacking Socs3 die before birth, so the researchers studied rodents that carried one normal and one defunct version of the gene--they make about half the normal amount of the protein. Injecting small doses of leptin produced little change in control mice but triggered the experimental animals to shed weight and burn fat, suggesting that the reduction in Socs3 quantities increased sensitivity to the hormone. Normal mice grew plump on a fatty diet, but the Socs3-altered rodents gained the same amount whether their meals were rich or lean. Moreover, gobbling lots of fat boosted blood quantities of glucose and insulin in the control animals--increases that can presage diabetes--but not in the experimental group.
Leptin works in the brain by latching onto a receptor, provoking enzymes to add a phosphate group to the protein Stat3. To determine whether reducing Socs3 concentrations increases this activity, the researchers measured the quantity of phosphate-toting Stat3 in the mice's brains. After 5 hours, the Socs3-deficient rodents carried about three times more in the hypothalamus than did control animals. Overall, the findings indicate that cutting Socs3 dosage boosts leptin's activity in the brain and improves the animals' responsiveness to the hormone. Drugs that impede the protein might counteract leptin resistance in people, Flier says. But meddling with Socs3 could be tricky, he says, because it helps regulate the immune system and might perform other tasks.
"This is a major step toward understanding the mechanism of leptin resistance," says neuroendocrinologist Abhiram Sahu of the University of Pittsburgh in Pennsylvania. The paper identifies a potentially fixable alteration that could explain why the brains of obese people don't heed the hormone, he says. However, leptin resistance can occur at sites other than the hypothalamus, says endocrinologist William Banks of the Veterans Affairs Medical Center in St. Louis, Missouri. And the hormone can also have trouble slipping across the blood-brain barrier. Researchers should determine whether Socs3 underlies either of these problems, he suggests. In any case, shackling the protein might help the brain and fat get back on speaking terms.
June 30, 2004
Suggested by Amir Sadighi Akha.
Science of Aging Knowledge Environment. ISSN 1539-6150