Researchers Uncover New Role for Gene in Maintaining Steady Weight

By Eric Sauter

Against the backdrop of the growing epidemic of obesity in the United States, scientists from the Florida campus of The Scripps Research Institute have made an important new discovery regarding a specific gene that plays an important role in keeping a steady balance between our food intake and energy expenditure. The study may help scientists better understand the keys to fighting obesity and related disorders such as diabetes.

The study, which was published in the November 25, 2011 print edition of The Journal of Biological Chemistry, focused on the melanocortin-3 receptor (MC3R), which normally responds to signals of nutrient intake.

“What we discovered was quite a surprise,” said Scripps Research Associate Professor Andrew Butler, who led the study. “We thought that the actions of the receptor expressed in the brain would be critical for metabolic homeostasis. However, what we found is that actions of the receptor expressed outside the brain appear to be equally important.”

The existence of drug targets in areas outside of the central nervous system (the body’s “periphery”) might help in the effort to develop drugs that influence metabolism without major side effects, Butler said.

The findings were made possible by the team’s development of a new transgenic animal model, where expression of the MC3R gene can be selectively “switched on” in different cell types.

In the study, the suppression of MC3R expression in the brain and peripheral tissues had a marked impact on metabolic homeostasis (equilibrium). Interestingly, mice expressing the MC3R gene in the brain only displayed an obese phenotype (physical appearance) similar to those where all types of expression was suppressed, indicating that actions of this receptor in the brain are not sufficient to protect against weight gain. The finding that loss of MC3R activity in the periphery impairs metabolic homeostasis is startling, Butler said, and point to a distinct role for MC3R signaling in the peripheral tissues. However, how the actions of these receptors impacts on obesity remains to be determined.

“It’s clear that these peripheral receptors are important and the new mouse model will let us explore that potential,” Butler said. 

The first author of the study, “Genetic dissection of melanocortin-3 receptor function suggests roles for central and peripheral receptors in energy homeostasis,” is Karima Begriche of Scripps Research. In addition to Butler and Begriche, other authors include Jari Rossi, Danielle Skorupa, Laura A. Solt, Brandon Young, and Thomas P. Burris from The Scripps Research Institute in Florida; Randall L. Mynatt and Jingying Zhang at the Pennington Biomedical Research Center, which is part of the Louisiana State University System; and Peter R. Levasseur and Daniel L. Marks at the Oregon Health & Science University. See http://www.jbc.org/content/early/2011/10/07/jbc.M111.278374.abstract?sid=8a17ce75-de95-45d1-b688-a039da52b5f1

The study was supported by National Institutes of Health and the Pennington Biomedical Research Foundation.

Send comments to: press@scripps.edu