Could fat be in the brain of the beholder? A new study shows that signals in the brain that warn appetite-modulating neurons of excess fat stores can be suppressed, making the brain unaware of the body's condition. The result: the body becomes completely ignorant about its own makeup and thus makes no attempt to increase energy expenditure or reduce appetite to help shave flab.

The new findings—published in this week's Cell Metabolism—could give hope to the 90 million obese people in the U.S., because it confirms a possible therapeutic target that could resensitize the brain so that it could recognize and take steps to prevent fat buildup.

The key to the body's tally of fat stores is the hormone leptin. The arcuate nucleus section of the hypothalamus (the brain region that connects the nervous and endocrine systems) senses leptin after it is secreted by fat cells. Obese people have high levels of leptin, but researchers have determined that, for some reason, the brain often develops an insensitivity to leptin in people who consumer high-fat diets, in essence allowing the body to ignore its own heft. Researchers at Brown University and the Oregon Health & Science University (OHSU) in Portland developed a mouse model to try to detect where the leptin signaling system breaks down during high-fat consumption. For 20 weeks—one quarter of an average mouse lifetime—the scientists fed one group of mice a high-fat diet. Sixty percent of these animals became obese and developed surging quantities of leptin. The other 40 percent stayed at the same weight and retained normal leptin levels.

Senior study author Michael Cowley, an OHSU neuroscientist, is not sure why all of the mice chowing down on fatty fare did not beef up. "These mice are inbred so that they are genetically identical," he says, speculating that "it could be an effect after birth—maybe the mother favors some over others."

The researchers tested leptin function in both sets of mice by removing the hypothalamus from each mouse. "In the lean animals, there was a dose-responsive effect of leptin," says Cowley, which means that more leptin caused increased production of chemical signals or neuropeptides that activate pathways to increase or decrease appetite. "In the obese mice, who showed no behavioral response to leptin, leptin also caused no change in the secretion of neuropeptides from the hypothalamus."

Normally, leptin binds to a receptor in the arcuate nucleus, triggering a cascade of chemical signals that culminate in the activation of SOCS-3, a suppressor that stops the reaction. The scientists determined that obese animals had an adequate quantity of leptin receptors, but that the quantity of SOCS-3 had risen, likely thwarting any activation of the fat hormone.

This finding was reinforced by the team's discovery that the chemicals usually triggered by leptin were still intact. When the researchers removed fat from the obese critters' diets, the bloated mice returned to their normal weights and there was renewed leptin sensitivity over the next 20 weeks. This indicates, Cowley says, that "only the primary leptin sensing cells are disabled in obesity; the rest of the neural pathway is intact: only one link in the chain is broken."

This suggests that a treatment for obesity could possibly be developed that decreases SOCS-3 levels in the brain thereby reactivating the leptin signaling system. Harvard Medical School professor Christian Bjorbaek says the new findings confirm earlier research tying SOCS-3 levels to leptin insensitivity. But he notes that "the experiments indicating that downstream neurocircuits are intact—and even hypersensitive—does point to a defect in the primary neurons that express leptin receptors as a potential cause of obesity in high-fat fed mice."

Cowley says that SOCS-3 could be a possible target for antiobesity drug development, but he points out that it is also an immune system modulator, which means that its function cannot and should not be completely blocked. A possible solution, he says, might be "a regionally targetable SOCS-3 inhibitor, something that was especially lipid soluble—so it concentrated in the brain—or a partial antagonist, something that inhibited SOCS-3 a bit, but not enough to cause an immune storm."