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Leptin breakthrough

Researchers identify and block leptin interferring protein

Epac1 could lead to the development of new drugs for obesity and diabetes
Xiaodong Cheng

Researchers from the University of Texas Medical Branch and the University of California have identified a protein that can interfere with the brain's response to leptin and created a compound that blocks the protein's action.

Reporting the journal Molecular and Cellular Biology, the authors explored the role of the protein, known as Epac1, in blocking leptin's activity in the brain. They found that mice which were genetically engineered to be unable to produce Epac1 had lower body weights, lower body fat percentages, lower blood-plasma leptin levels and better glucose tolerance than normal mice.

When the researchers used a specially developed Epac inhibitor to treat brain-slice cultures taken from normal laboratory mice, they found elevated levels of proteins associated with greater leptin sensitivity.

Similar results were seen in the genetically engineered mice that lacked the Epac1 gene. In addition, normal mice treated with the inhibitor had significantly lower levels of leptin in their blood plasma, an indication that Epac1 also affected their leptin levels.

"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. "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."

Cheng and his colleagues suspected a connection between Epac1 and leptin because Epac1 is activated by cyclic AMP, a signalling molecule linked to metabolism and leptin production and secretion. Cyclic AMP is tied to a multitude of other cell signalling processes, many of which are targeted by current drugs.

He believes that understanding how it acts through Epac1 (and another form of the protein called Epac2) will also generate new pharmaceutical possibilities, including a drug therapy that will help fight obesity and diabetes.

"We refer to these Epac inhibitors as pharmacological probes, and while they are still far away from drugs, pharmaceutical intervention is always our eventual goal," said Cheng. "We were the first to develop Epac inhibitors, and now we're working very actively to modify them and improve their properties.”

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