Their findings, reported in the July 5 issue of Cell Metabolism, suggest a novel approach for duplicating leptin's actions when the body no longer responds to the hormone.
Fat cells release leptin into the bloodstream. The hypothalamus "reads" the amount of circulating leptin and uses this information to regulate appetite, metabolism and other processes. "Leptin is known to bind to cell-surface receptors in the hypothalamus and then to activate various other cellular signals including a molecule called STAT3--but the role of STAT3 in mediating leptin's multiple physiological effects was still unknown," says Dr. Luciano Rossetti, the study's senior author and the director of the Diabetes Research and Training Center at Einstein.
To learn whether STAT3 mediates some of leptin's activities, "we devised a technique for inactivating STAT3 with pinpoint accuracy in the hypothalamus and observing the results in laboratory animals when we administered leptin," says Dr. Rossetti. "Our tool for rapidly inactivating STAT3 was a cell-permeable peptide (short protein) that we infused into specific areas of the hypothalamus using fine needles. This technique can serve as a model for investigating all types of signaling pathways in selective regions of the brain."
The researchers found that STAT3 production is essential for leptin's best-known action: acutely reducing food intake. Since obesity occurs when people become resistant to leptin's "curb your eating" message, this finding suggests that bypassing leptin and directly activating STAT3 may allow one to normalize appetite and produce other health benefits as well.
As it does with appetite, leptin also influences glucose metabolism. Aberrant glucose metabolism causes the hypergylcemia (high blood-sugar levels) that is the hallmark of diabetes. "There had been considerable controversy as to whether leptin controls glucose metabolism through STAT3 production or not," says Dr. Rossetti. "Using our technique for blocking STAT3, we were able to show that STAT3 is absolutely necessary for the acute effect of leptin on glucose metabolism."
Leptin is also known to influence fertility. Women with very little body fat--elite female athletes, for example--may stop menstruating and experience temporary infertility. This is largely due to inadequate secretion of leutenizing hormone and follicle stimulating hormone by the pituitary gland--which in turn is caused by the near-disappearance of leptin from the bloodstream. A recent study showed that low doses of leptin can restore the menstrual cycle in such women. Using their STAT3-blocking technique, the Einstein researchers showed that this acute effect of leptin depends on the activation of STAT3.
"This work has shown that STAT3 is fundamentally important for expressing several of leptin's acute effects," says Dr. Rossetti. "Since we now fully appreciate the important role of STAT3 in leptin's metabolic actions, strategies designed to restore the effects of leptin on STAT3 should achieve considerable health benefits. An obvious target is obesity, where the big problem is leptin resistance. But in addition, our findings suggest that selectively turning on STAT3 may help prevent diabetes by improving glucose metabolism and help restore fertility as well."
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