Vanderbilt University researchers have discovered a new critical component in the obesity pathway.
The findings, published last month in Science, reveal melanocortin receptor accessory protein 2 (MRAP2) to be an important regulator of the melanocortin pathway in the brain. This pathway is involved in energy homeostasis, balance of food intake and energy expenditure, and regulation of body weight.
Previously, impaired function of the melanocortin-4 receptor (MC4R) was identified as the most common single gene cause of severe early-onset obesity. Restoring the function of this receptor has been a target for development of new drugs to treat obesity.
“Identification of a native modulator of the MC4R receptor that can either diminish or augment activity introduces a new level of complexity in this energy homeostasis pathway,” said Roger Cone, Ph.D., chair of Molecular Physiology and Biophysics.
“This study has led us to hypothesize that the MRAP2 proteins control the developmental appearance of regulated feeding by tuning the activity of the MC4R, and their function appears conserved from fish to mice to humans,” he said.
Cone, who also is the Joe C. Davis Professor of Biomedical Science, co-first authors Julien Sebag, Ph.D., and Chao Zhang, Ph.D., and their colleagues investigated the function of MRAP2 using zebrafish and human cell culture.
Unlike mammals, zebrafish have two slightly different “isoforms” of the MRAP2 protein. The researchers discovered that the isoforms are expressed differentially during development and have divergent effects on MC4R.
MRAP2a is expressed predominantly during embryogenesis, where it stimulates growth by blocking function of the MC4R. In vitro studies in human cells revealed that MRAP2a likely stabilizes receptor in a non-functional state, but does not change expression of the receptor.
Conversely, MRAP2b is expressed primarily in the adult zebrafish. Human cell culture experiments demonstrated that MRAP2b significantly increases expression of MC4R at the cell surface.
Further, MRAP2b expression amplified the activation of the receptor by alpha-melanocyte-stimulating hormone (alpha-MSH) by 17-fold. The researchers demonstrated that the mammalian counterpart, MRAP2, has a similar pharmacological activity and does not reach full expression in the mouse until around weaning.
Indeed, the function of zebrafish MRAP2b is similar to mammalian MRAP2. An accompanying Science paper in this issue demonstrates that loss of function of MRAP2 in mice leads to obesity and functional MRAP2 increases of the responsiveness of MC4R.
These studies continue Cone’s innovative work in elucidating the melanocortin system pathway he discovered.
This research was supported by National Institutes of Health grants DK075721, DK070332, DK019974 and DK091055, United States-Israel Binational Agricultural Research and Development Fund, and Vanderbilt Diabetes Research Training Center grant DK020593.
— by Courtney M. Campbell