Researchers identify and block protein that interferes with appetite-suppressing hormone

April 17, 2013, University of Texas Medical Branch at Galveston

Ever since the appetite-regulation hormone called leptin was discovered in 1994, scientists have sought to understand the mechanisms that control its action. It was known that leptin was made by fat cells, reduced appetite and interacted with insulin , but the precise molecular details of its function —details that might enable the creation of a new treatment for obesity—remained elusive.

Now, University of Texas Medical Branch at Galveston researchers have revealed a significant part of one of those mechanisms, identifying a protein that can interfere with the brain's response to leptin. They've also created a compound that blocks the protein's action—a potential forerunner to an anti-.

In experiments with mice fed a high-fat diet, scientists from UTMB and the University of California, San Diego explored the role of the protein, known as Epac1, in blocking leptin's activity in the brain. They found that mice genetically engineered to be unable to produce Epac1 had lower body weights, lower body fat percentages, lower blood- levels and better than normal mice.

When the researchers used a specially developed "Epac inhibitor" to treat brain-slice cultures taken from normal , 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 —an indication that Epac1 also affected their .

"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, available on the journal's Web site at http://mcb.asm.org/content/33/5.toc. "The 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 signaling molecule linked to metabolism and leptin production and secretion. Cyclic AMP is tied to a multitude of other cell signaling processes, many of which are targeted by current drugs. Cheng believes that understanding how it acts through Epac1 (and another form of the protein called Epac2) will also generate new pharmaceutical possibilities—possibly 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," Cheng said. "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."

Explore further: Voluntary exercise by animals prevents weight gain, despite high-fat diet

Related Stories

Voluntary exercise by animals prevents weight gain, despite high-fat diet

May 18, 2011
(Medical Xpress) -- University of Cincinnati (UC) researchers have found that animals on a high-fat diet can avoid weight gain if they exercise.

Scientists discover a protein that contributes to obesity

May 4, 2011
Weizmann Institute scientists have added another piece to the obesity puzzle, showing how and why a certain protein that is active in a small part of the brain contributes to weight gain. This research appeared today in Cell ...

Recommended for you

Researchers devise decoy molecule to block pain where it starts

January 16, 2018
For anyone who has accidentally injured themselves, Dr. Zachary Campbell not only sympathizes, he's developing new ways to blunt pain.

Scientists unleash power of genetic data to identify disease risk

January 16, 2018
Massive banks of genetic information are being harnessed to shed new light on modifiable health risks that underlie common diseases.

Blood-vessel-on-a-chip provides insight into new anti-inflammatory drug candidate

January 15, 2018
One of the most important and fraught processes in the human body is inflammation. Inflammatory responses to injury or disease are crucial for recruiting the immune system to help the body heal, but inflammation can also ...

Molecule produced by fat cells reduces obesity and diabetes in mice

January 15, 2018
UC San Francisco researchers have discovered a new biological pathway in fat cells that could explain why some people with obesity are at high risk for metabolic diseases such as type 2 diabetes. The new findings—demonstrated ...

Obese fat becomes inflamed and scarred, which may make weight loss harder

January 12, 2018
The fat of obese people becomes distressed, scarred and inflamed, which can make weight loss more difficult, research at the University of Exeter has found.

Optimized human peptide found to be an effective antibacterial agent

January 11, 2018
A team of researchers in the Netherlands has developed an effective antibacterial ointment based on an optimized human peptide. In their paper published in the journal Science Translational Medicine, the group describes developing ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.