MRAP2 regulates ghrelin receptor signaling and hunger sensing

Dollada Srisai,Julien A Sebag,Alix A J Rouault,Nicole A Pearson,Terry C Yin,Justin L Grobe,Abigail A Lee

doi:10.1038/s41467-017-00747-6

Dollada Srisai, Julien A Sebag + Show 5 more

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https://doi.org/10.1038/s41467-017-00747-6

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Journal: Nature Communications	Publication Date: Sep 28, 2017
Citations: 61	License type: open-access

Affiliation: S.P.E.C.I.E.S., University of Iowa

Abstract

Ghrelin is the only known circulating orexigenic hormone. It is primarily secreted by the stomach and acts at its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), in the hypothalamus to signal hunger and promote food intake. The melanocortin receptor accessory protein 2 (MRAP2) was previously shown to regulate energy homeostasis through the modulation of the activity of the melanocortin-4 receptor and prokineticin receptors. In this study we identify MRAP2 as a partner of ghrelin-GHSR1a signaling. We show that MRAP2 interacts with GHSR1a and potentiates ghrelin-stimulated signaling both in vitro and in vivo. We demonstrate that in the absence of MRAP2, fasting fails to activate agouti-related protein neurons. In addition, we show that the orexigenic effect of ghrelin is lost in mice lacking MRAP2. Our results suggest that MRAP2 is an important modulator of the energy homeostasis machinery that operates through the regulation of multiple GPCRs throughout the hypothalamus.

Highlights

Ghrelin is the only known circulating orexigenic hormone
In this study we investigated if melanocortin receptor accessory protein 2 (MRAP2) modulates ghrelin signaling in vitro and in vivo, and conclude that MRAP2 interacts with growth hormone secretagogue receptor 1a (GHSR1a) and is an important component of the ghrelin receptor signaling complex, establishing that in addition to being a regulator of satiety sensing through the modulation of MC4R and PKR1 activity, MRAP2 promotes hunger sensing by potentiating ghrelin signaling
While we observed no significant difference in daily food intake (Fig. 1b) or accumulated food intake (Fig. 1g) between WT and Mrap[2] KO mice, we found that mice lacking MRAP2 eat about 30% less food compared to their WT littermates in the day following a 24 h fast (Fig. 1h), suggesting that MRAP2 is important for hunger sensing and that Mrap[2] KO mice experience a weaker drive to eat following a fast

Summary

Introduction

Ghrelin is the only known circulating orexigenic hormone It is primarily secreted by the stomach and acts at its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), in the hypothalamus to signal hunger and promote food intake. Ghrelin acts through its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), a G-protein-coupled receptor (GPCR) expressed in the hypothalamus, in particular in orexigenic agouti-related protein (AGRP) neurons[5,6,7,8]. MRAP2 is highly expressed in the hypothalamus where it is known to regulate the activity of the melanocortin-4 receptor[10, 11] and the prokineticin receptors[12], GPCRs, that signal satiety and are required for the proper control of food intake and energy expenditure[12,13,14,15,16]. In this study we investigated if MRAP2 modulates ghrelin signaling in vitro and in vivo, and conclude that MRAP2 interacts with GHSR1a and is an important component of the ghrelin receptor signaling complex, establishing that in addition to being a regulator of satiety sensing through the modulation of MC4R and PKR1 activity, MRAP2 promotes hunger sensing by potentiating ghrelin signaling

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