Attractin-like protein 1 is an essential partner of MC4R to regulate body weight

Paul Buscaglia; Kate R. Bowman; Katherine Lawler; Ciria C. Hernandez; Jacopo Scotucci; Rebecca Bounds; Julia M. Keogh; Elana Henning; Roger D. Cone; I. Sadaf Farooqi; Julien A. Sebag

doi:10.1038/s41467-026-77897-z

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Attractin-like protein 1 is an essential partner of MC4R to regulate body weight

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Attractin-like protein 1 is an essential partner of MC4R to regulate body weight

Paul Buscaglia, Kate R. Bowman, Katherine Lawler, Ciria C. Hernandez, Jacopo Scotucci, Rebecca Bounds, Julia M. Keogh, Elana Henning, Roger D. Cone, I. Sadaf Farooqi, …

Nature communications

09/22/2026

DOI: 10.1038/s41467-026-77897-z

PMCID: PMC13691095

PMID: 42918796

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Abstract

The melanocortin 4 receptor (MC4R) plays a critical role in the central control of energy homeostasis, and its disruption causes severe early-onset obesity. MC4R signaling is tightly regulated by endogenous agonists and antagonists, as well as the accessory protein MRAP2. The single transmembrane protein attractin-like protein 1 (ATRNL1) is a known interactor of MC4R, however, its effect on MC4R signaling and physiological function is not well understood. Here we show that ATRNL1 interacts with MC4R to amplify its signaling in cells and that expression of ATRNL1 potentiates agonist-induced activation of MC4R neurons. Deletion of Atrnl1 in MC4R neurons increased food intake and body weight in rodents. In exomes from 1,623 children with severe early-onset obesity, we identified multiple rare ATRNL1 variants that impair ATRNL1-mediated regulation of MC4R signaling. Cumulatively, these findings establish ATRNL1 as an important regulator of mammalian energy homeostasis.

Details

Title: Subtitle: Attractin-like protein 1 is an essential partner of MC4R to regulate body weight
Creators: Paul Buscaglia - University of Michigan
Kate R. Bowman - University of Iowa
Katherine Lawler - University of Cambridge
Ciria C. Hernandez - University of Michigan
Jacopo Scotucci - University of Cambridge
Rebecca Bounds - University of Cambridge
Julia M. Keogh - University of Cambridge
Elana Henning - University of Cambridge
Roger D. Cone - University of Michigan
I. Sadaf Farooqi - University of Cambridge
Julien A. Sebag - University of Michigan
Resource Type: Journal article
Publication Details: Nature communications
DOI: 10.1038/s41467-026-77897-z
PMID: 42918796
PMCID: PMC13691095
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: Springer Nature
Language: English
Electronic publication date: 09/22/2026
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9985238283402771

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