The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the prokineticin receptor-1

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Abstract

The Melanocortin Receptor Accessory Protein 2 (MRAP2) is an important regulator of energy homeostasis and its loss causes severe obesity in rodents. MRAP2 mediates its action in part through the potentiation of the MC4R, however, it is clear that MRAP2 is expressed in tissues that do not express MC4R, and that the deletion of MRAP2 does not recapitulate the phenotype of Mc4r KO mice. Consequently, we hypothesized that other GPCRs involved in the control of energy homeostasis are likely to be regulated by MRAP2. In this study we identified PKR1 as the first non-melanocortin GPCR to be regulated by MRAP2. We show that MRAP2 significantly and specifically inhibits PKR1 signaling. We also demonstrate that PKR1 and MRAP2 co-localize in neurons and that Mrap2 KO mice are hypersensitive to PKR1 stimulation. This study not only identifies new partners of MRAP2 but also a new pathway through which MRAP2 regulates energy homeostasis.

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Anna L Chaly

Carver College of Medicine, Pappajohn Biomedical Institute, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, United States

Competing interests
The authors declare that no competing interests exist.
Dollada Srisai

Carver College of Medicine, Pappajohn Biomedical Institute, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, United States

Competing interests
The authors declare that no competing interests exist.
Ellen E Gardner

Carver College of Medicine, Pappajohn Biomedical Institute, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, United States

Competing interests
The authors declare that no competing interests exist.
Julien A Sebag

Carver College of Medicine, Pappajohn Biomedical Institute, Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, United States

For correspondence
julien-sebag@uiowa.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (# 4061063 (Sebag)) of the University of Iowa. The protocol was approved by the Office of the IACUC at the University of Iowa. All surgery was performed under ketamine/ xylazine anesthesia, and every effort was made to minimize suffering including the use of post surgery buprenorphine.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.