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Block protein of the appetite reducing hormone Leptin identified
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The appetite-regulation hormone called leptin was discovered in 1994, and ever since then scientists have been trying to understand the mechanisms that control and direct its action. It was known that leptin was produced by fat cells, that it reduced appetite and interacted with insulin, but the precise molecular schematics of its function, details that might enable the creation of a new treatment for obesity, remained unsolved. The discovery and other recent research into leptin and obesity-related genes can be found here. Reports about the research into linking neural activity and brain physiology with obesity can be found here.

University of Texas Medical Branch at Galveston scientists have uncovered a significant part of one of the leptin-related mechanisms, identifying a protein that can interfere with the brain's response to leptin. They've also created an experimental compound that blocks the protein's action, which can be a potential precursor to an anti-obesity drug.

The experiments were done with mice that were fed a high-fat diet; scientists from UTMB and the University of California, San Diego collaborated to explore the role of the newly identified protein, known as Epac1, in interfering and blocking leptin's activity in the brain. They found that mice who were genetically engineered as to be unable to produce Epac1 had significantly lower body weights, lower body fat percentages, lower blood-plasma leptin levels and an increased glucose tolerance compared to normal mice.

Then the researchers applied a specially developed "Epac inhibitor" onto brain-slice cultures taken from normal laboratory mice, and they found that elevated levels of proteins were associated with greater leptin sensitivity. Similar results were shown in the genetically engineered mice that lacked the Epac1 gene. Normal mice treated with the inhibitor had marked lower levels of leptin in their blood plasma, which is 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. 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." - 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 research team had long suspected there to be a connection between Epac1 and leptin because Epac1 is activated by cyclic AMP, a signaling molecule which is severely linked to metabolism and leptin production and secretion, as shown in previous studies. Cyclic AMP has already been tied to a multitude of other cell signaling processes, many of which are targeted by a multitude of current drugs. Cheng and his team believe that exploring how cyclic AMP and Epac1 and its alternative form Epac2 interact and compile might provide great potential for research into the leptin metabolism, and eventually provide with a long-sought after achievement – A potential drug to treat obesity.

"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. We were the first to develop Epac inhibitors, and now we're working very actively with Dr. Jia Zhou, a UTMB medicinal chemist, to modify them and improve their properties. In addition, we are collaborating with colleagues at the NIH National Center for Advancing Translational Sciences in searching for more potent and selective pharmacological probes for Epac proteins." – Said Dr. Cheng


This was a large collaboration paper with many authors. Other authors of the Molecular and Cellular Biology paper include research associates Jingbo Yan, Jingna Wei and Sonja Stutz, research scientists Fang C. Mei and Igor Patrikeev, graduate assistant Yaohua Hu, visiting physician Dapeng Hao, professors Massoud Motamedi and Kathryn A. Cunningham, associate professor Kelly T. Dineley and assistant professor Jonathan D. Hommel, all from UTMB. Authors from the University of California, San Diego include postdoctoral fellows Hongqiang Cheng and Dieu Hung Lao, and professor Ju Chen.

Resouces:
J. Yan, F. C. Mei, H. Cheng, D. H. Lao, Y. Hu, J. Wei, I. Patrikeev, D. Hao, S. J. Stutz, K. T. Dineley, M. Motamedi, J. D. Hommel, K. A. Cunningham, J. Chen, X. Cheng.Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1. Molecular and Cellular Biology, 2012
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Block protein of the appetite reducing hormone Leptin identified00