AgRP and POMC Neurons Are Hypophysiotropic and Coordinately Regulate Multiple Endocrine Axes in a Larval Teleost

Abstract

SUMMARY Plasticity in growth and reproductive behavior is found in many vertebrate species, but is common in male teleost fish. Typically, “bourgeois” males are considerably larger and defend breeding territories while “parasitic” variants are small and use opportunistic breeding strategies. The P locus mediates this phenotypic variation in Xipophorus and encodes variant alleles of the melanocortin-4 receptor (MC4R). However, deletion of the MC4R has modest effects on somatic growth and reproduction in mammals, suggesting a fundamental difference in the neuroendocrine function of central melanocortin signaling in teleosts. Here we show in a teleost that the hypothalamic proopiomelanocortin and AgRP neurons are hypophysiotropic, projecting to the pituitary to coordinately regulate multiple pituitary hormones. Indeed, AgRP-mediated suppression of MC4R appears essential for early larval growth. This identifies the mechanism by which the central melanocortin system coordinately regulates growth and reproduction in teleosts, and suggests it is an important anatomical substrate for evolutionary adaptation.

Development of an Assay for High-Throughput Energy Expenditure Monitoring in the Zebrafish

“…Our group has previously shown that AgRP knockdown in the zebrafish results in decreased body size, dependent on effects at the MC4R. 13 We show here that AgRP knockdown increases energy expenditure in both wild-type (WT) and MC4R mutant zebrafish. We further show that MC3R morpholino eliminates the response to AgRP knockdown.…”

“…Melanocortin-4 receptor (MC4R) null zebrafish (allele: sa0149) were originally generated and provided by the Wellcome Trust Sanger Institute. MC4R mutants were identified by genotyping as previously described, 13 and reared identically to wild-type fish. MC4R -/-, +/-, and +/+ embryos were created by +/-X +/-breedings.…”

Gene Amplification and Functional Diversification of Melanocortin 4 Receptor at an Extremely Polymorphic Locus Controlling Sexual Maturation in the Platyfish

“…Selection parameter v was calculated as the nonsynonymous substitution rate/synonymous substitution rate (dN/dS) ratio using CodeML from the PAML 3.15 package (Yang 1997). Sánchez et al 2009;Schjolden et al 2009;Wan et al 2012;Zhang et al 2012;Sebag et al 2013).…”

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

“…Mutations in the gene encoding MC4R are the most common monogenic cause of severe early-onset obesity in humans (1). In the zebrafish, as in mammals, MC4R is prominently involved in the regulation of energy homeostasis and somatic growth (6). Dominant negative mutations in MC4R are a natural cause of increased growth rate and final size in some teleost species (5).…”

“…Dominant negative mutations in MC4R are a natural cause of increased growth rate and final size in some teleost species (5). An artificially induced increase in MC4R activity early in the development of the zebrafish embryo causes a decrease in growth, a decrease in growth hormone gene expression, and a compensatory increase in growth hormone–releasing hormone ( ghrh ) gene expression (6), thus providing quantitative assays for MC4R activity in vivo. The melanocortin receptors have been shown to interact with the melanocortin receptor accessory proteins MRAP1 and MRAP2 (7–13), which are single-transmembrane proteins that form unusual antiparallel homo- and heterodimers (7–9).…”