Abstract
The melanocortin receptor 4 (MC4R) signaling system consists of MC4R, MC4R ligands [melanocyte-stimulating hormone (MSH), adrenocorticotropin (ACTH), agouti-related protein (AgRP)], and melanocortin-2 receptor accessory protein 2 (MRAP2), and it has been proposed to play important roles in feeding and growth in vertebrates. However, the expression and functionality of this system have not been fully characterized in teleosts. Here, we cloned tilapia MC4R, MRAP2b, AgRPs (AgRP, AgRP2), and POMCs (POMCa1, POMCb) genes and characterized the interaction of tilapia MC4R with MRAP2b, AgRP, α-MSH, and ACTH in vitro. The results indicate the following. (1) Tilapia MC4R, MRAP2b, AgRPs, and POMCs share high amino acid identity with their mammalian counterparts. (2) Tilapia MRAP2b could interact with MC4R expressed in CHO cells, as demonstrated by Co-IP assay, and thus decrease MC4R constitutive activity and enhance its sensitivity to ACTH1-40. (3) As in mammals, AgRP can function as an inverse agonist and antagonist of MC4R, either in the presence or absence of MRAP2b. These data, together with the co-expression of MC4R, MRAP2b, AgRPs, and POMCs in tilapia hypothalamus, suggest that as in mammals, ACTH/α-MSH, AgRP, and MRAP2 can interact with MC4R to control energy balance and thus play conserved roles in the feeding and growth of teleosts.
Highlights
There has been increasing evidence showing that the melanocortin receptor 4 (MC4R) signaling system is crucial in the control of food intake and energy balance in the hypothalamus of vertebrates [1,2,3,4,5,6]
These data, together with the co-expression of MC4R, MRAP2b, agouti-related peptide (AgRP), and POMCs in tilapia hypothalamus, suggest that as in mammals, ACTH/α-melanocyte-stimulating hormone (MSH), AgRP, and melanocortin receptor 2 accessary protein 2 (MRAP2) can interact with MC4R to control energy balance and play conserved roles in the feeding and growth of teleosts
This signaling system consists of MC4R, MC4R ligands [α-melanocyte-stimulating hormone (α-MSH); adrenocorticotropin (ACTH), and agouti-related peptide (AgRP)], and melanocortin receptor 2 accessary protein 2 (MRAP2) [2,5]. α-MSH and ACTH are derived from the proopiomelanocortin (POMC) precursor and can activate MC4R and increase intracellular cAMP levels, while AgRP can act either as an antagonist to block α-MSH/ACTH action on MC4R, or as an inverse agonist to decrease the basal constitutive activity of MC4R in the absence of α-MSH/ACTH [1,7,8]
Summary
There has been increasing evidence showing that the melanocortin receptor 4 (MC4R) signaling system is crucial in the control of food intake and energy balance in the hypothalamus of vertebrates [1,2,3,4,5,6]. MRAP2 is a single-pass transmembrane protein and can form an antiparallel homodimer [9] It can decrease the basal constitutive activity of MC4R, and modulate its sensitivity and selectivity toward its ligands [2,5]. It is clear that in mammals, all the components of the MC4R signaling system are expressed in the hypothalamus and play a key role in the regulation of food intake, growth, and energy balance. The mutation of MRAP2 in humans and mice causes early-onset severe obesity [2]. All these findings support the notion that MC4R, α-MSH/ACTH, AgRP, and MRAP2 can form a complex interaction network to regulate the feeding, energy balance, and growth of animals [2,5]
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