1698-P: Regulation of the Melanocortin-4 Receptor (MC4R) by Attractin-Like Protein 1 (ATRNL1)

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Introduction and Objective: The Melanocortin-4 Receptor (MC4R) plays a central role in the regulation of energy homeostasis. Mutations in MC4R are responsible for up to 6% of early onset obesity in humans and deletion of MC4R in mice results in severe obesity due to hyperphagia. MC4R is a GPCR expressed in different region of the brains including the paraventricular nucleus of the hypothalamus. Stimulation of MC4R by its agonist αMSH and inhibition by its endogenous inverse agonist AGRP result in inhibition or stimulation of food intake respectively. MC4R is known to interact with two single transmembrane proteins, the Melanocortin Receptor Accessory Protein 2 (MRAP2) and Attractin Like Protein 1 (ATRNL1). Whereas MRAP2 has been shown to promote MC4R signaling in vitro and in vivo, the pharmacological and physiological relevance of ATRNL1 for MC4R signaling and actions is not known. Our objective is to identify the role of ATRNL-1 in MC4R signaling and function. Methods: This study utilizes an in vitro model of kinetic MC4R signaling and trafficking to evaluate the effect of ATRNL1 on MC4R activity. We generated an ATRNL1FLOX mouse to study the role of ATRNL1 in MC4R neurons in vivo. Results: In this study, we show that ATRNL1 interacts with MC4R, potentiates its signaling and inhibits beta-arrestin recruitment to the receptor. Deletion of ATRNL1 in MC4R neurons resulted in hyperphagia and increased body weight both on standard and high fat diets. Deletion of ATRNL1 in MC4R neurons also resulted in a decreased activation of those neurons in response to injection of the MC4R agonist MTII. Conclusion: Our results identify ATRNL1 as an important regulatory protein of MC4R and a required component of the energy homeostasis machinery. Disclosure P. Buscaglia: None. J. Sebag: None.