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Drugs currently on the market but used for other purposes helped plump mice shed pounds by upping their response to the appetite-suppressing hormone leptin, according to a new study. Researchers say the findings offer new hope in the search for weight-loss meds that exploit the hunger-dampening hormone, first discovered some 13 years ago.
"Leptin is a protein secreted from the adipocytes (fat cells)," says Umut Ozcan, an endocrinologist at Children's Hospital in Boston, Mass., and senior author of the study published today in the journal Cell Metabolism. "When fat cells release this hormone, it travels to an area [in the brain] called the hypothalamus," which controls appetite. Upon entering the hypothalamus, Ozcan says, the hormone alerts brain cells, or neurons, that the body has taken in enough food to meet its energy needs so there's no reason to keep eating. He says that most obese people have developed a resistance to leptin, which means that the hypothalamus no longer heeds its messages to stop chowing down.
"When leptin goes to knock on the door [to try to deliver its message to the neurons in the hypothalamus], they don't respond," Ozcan says. This triggers a feeling of constant hunger, causing people to overeat, leading to even greater leptin resistance: "It becomes a vicious cycle," he says.
Ozcan and his colleagues sought to reverse leptin resistance in mice by using two drugs already approved by the Food and Drug Administration (FDA) to treat other disorders: 4-Phenyl Butyric Acid (PBA), an Rx that helps treat conditions that hinder the body's ability to get rid of nitrogen (a waste product normally excreted in urine) in the blood, and Tauroursodeoxycholic acid (TUDCA), used to treat liver ailments such as primary billiary cirrosis, a disease in which the ducts are destroyed that produce bile, which breaks down fat in the body.
Both of these drugs are classified as "chemical chaperones," which are designed to improve the function of endoplasmic reticulum (ER), a structure inside the cells that is responsible for making proteins that carry out a variety of functions. For some unknown reason, Ozcan says, the ER in obese people becomes overtaxed and fails to produce sufficient amounts of protein, which, for some unknown reason, de-activates the cells' leptin receptors.
When researchers gave chunky mice leptin injections along with PBA or TUDCA, the animals rapidly dropped weight. After 30 days on the drugs, they had lost at least 16 percent of their body weight, according to Ozcan. The $64,000 (or, perhaps, $64 million) question: will it work in people? Not sure, he says, but adds that one day he hopes to conduct clinical trials along with other researchers.
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