When the appetite suppression hormone leptin was found in 1994 researchers hoped that it would quickly lead to new pharmaceuticals that could combat the obesity epidemic. Leptin is made by fat cells and tells the brain that you have enough stored energy to devote to things like exercise, going through puberty, and pregnancy.
To test exactly what the hormon does, scientists bred mice that were unable produce any leptin. The mice grew fat and became many times their normal weight.
Close to 20 years after the discovery of the protein, there is still no treatment that makes use of leptin. This is because there is an upper limit that the brain detects, and past that it stops responding — in other words, your body can only use so much leptin. When people who genetically can’t produce leptin are given injections, they eat less and become thinner. But when obese people with normal levels of leptin are given injections it does nothing.
But now, a research team out of the University of Texas Medical Branch at Galveston has attacked the issue from another angle. The scientists have uncovered a mechanism in the brain that interferes with the brain’s response to leptin. The protein they found, Epac1, actually blocks leptin in the brain, so they decided to remove the blocker and let the brain see all the leptin it can.
Scientists fed mice that didn’t produce Epac1 a high-fat diet and compared them with regular mice on the same diet. While normal mice on a high fat diet become obese, increase their body fat percentages, increase their blood leptin levels and have worse glucose tolerance (diabetes), the mice without Epac1 had the reverse. Mice without the blocking protein stayed thinner, had less body fat, had less leptin in their blood, and displayed fewer symptoms of diabetes.
A comparison of a mouse unable to produce leptin, resulting in obesity (left), and a normal mouse (right) (Credit: ornl.gov)
When the researchers treated mice with a drug that blocked Epac1, they saw that leptin levels were far lower in the blood because the brain became far more sensitive to the leptin hormone.
“We found that we can increase leptin sensitivity by creating mice that lack the genes for Epac1 or through a pharmacological intervention with our Epac inhibitor,” said UTMB professor Xiaodong Cheng, lead author of a paper on the study that recently appeared on the cover of Molecular and Cellular Biology. “The knockout mice gave us a way to tease out the function of the protein, and the inhibitor served as a pharmacological probe that allowed us to manipulate these molecules in the cells.”
The research group is working with medicinal chemists and researchers at the National Institutes of Health to search for more potent and selective pharmacological interventions for blocking Epac proteins.
In a few years the ability to control metabolism and huger through medications might finally be a reality.
The research was published in the journal Molecular and Cellular Biology and can be found here.
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