Developmental Control of the Melanocortin-4 Receptor by MRAP2 Proteins in Zebrafish

Abstract

The melanocortin-4 receptor (MC4R) is essential for control of energy homeostasis in vertebrates. MC4R interacts with melanocortin receptor accessory protein 2 (MRAP2) in vitro, but its functions in vivo are unknown. We found that MRAP2a, a larval form, stimulates growth of zebrafish by specifically blocking the action of MC4R. In cell culture, this protein binds MC4R and reduces the ability of the receptor to bind its ligand, α–melanocyte-stimulating hormone (α-MSH). A paralog, MRAP2b, expressed later in development, also binds MC4R but increases ligand sensitivity. Thus, MRAP2 proteins allow for developmental control of MC4R activity, with MRAP2a blocking its function and stimulating growth during larval development, whereas MRAP2b enhances responsiveness to α-MSH once the zebrafish begins feeding, thus increasing the capacity for regulated feeding and growth.

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“…In the adult stage of the zebrafish life cycle, the expression levels of the mrap2a gene decline, and the expression levels of the mrap2b gene increase. Sebag et al (2013) found that co-expression of zebrafish MRAP2b and zebrafish MC4R in HEK-293 cells increases the sensitivity of MC4R for α-MSH; the same response was found in the study by Asai et al (2013). Regulating food intake appears to improve the fitness of adult zebrafish (Sebag et al 2013).…”

“…Sebag et al (2013) found that co-expression of zebrafish MRAP2b and zebrafish MC4R in HEK-293 cells increases the sensitivity of MC4R for α-MSH; the same response was found in the study by Asai et al (2013). Regulating food intake appears to improve the fitness of adult zebrafish (Sebag et al 2013). These results are of interest not only because they present a function for MRAP2, but they also suggest that functional variants of MRAP2 may be present in other vertebrates besides the zebrafish.…”

“…The zebrafish genome has two MRAP2 paralogs, MRAP2a and MRAP2b (Agulleiro et al 2010). Sebag et al (2013) observed that during the larval stage of zebrafish development, a period when growth is a primary objective, MRAP2a will interact with MC4R to lower activation of this receptor, and as a result the suppression of feeding via the MC4R circuit is decrease. This mechanism would allow the larval zebrafish to grow faster.…”

“…The MC3R neuronal circuit is involved with the control of ingestive behaviors and regulation of metabolic expenditure/homeostasis (Renquist et al 2011, Begriche et al 2013, whereas the MC4R circuit in the CNS regulates satiety (Cone 2006). The neuronal MC4R and MC3R circuits in the hypothalamus are of particular interest due to the fact that the mrap2 gene is expressed in this region of the brain in organisms as diverse as mice (Asai et al 2013) and zebrafish (Sebag et al 2013).…”

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“…However, though they could not demonstrate the direct action of the zebrafish AgRP protein as a competitive antagonist of the melanocortin receptors, the authors showed that the positive response to α-melanocyte stimulating hormone (α-MSH) by zebrafish MC3R, MC4R and MC5bR transfected cells could be antagonized with mouse-AgRP. Further research on this pathway revealed an in vivo interaction of MC4R with two forms of melanocortin receptor accessory protein 2 (MRAP2) in zebrafish [103] . In cell culture, MRAP2a binds to MC4R and reduces its ability to bind to its ligand αMSH, and in vivo, MRAP2a is expressed during larval stages and stimulates growth by blocking the action of MC4R.…”