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. This work was supported by a Wellcome Principal Research Fellowship (207462/Z/17/Z), the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Center, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment, the Leducq Foundation grant, and a NIHR Senior Investigator Award (all to I.S.F.). Part of this research has been conducted using the UK Biobank Resource under Application Number 53821, for which analyses were conducted on the Research Analysis Platform.
The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or the Department of Health and Social Care. Use of the U-M CCG SyncroPatch was supported in part by NIH High End Instrumentation grant, 1S10OD025203-01. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA Paul Buscaglia, Kate R.
Sebag Elizabeth Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, USA Paul Buscaglia, Kate R. Sebag Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, United Kingdom Katherine Lawler, Jacopo Scotucci, Rebecca Bounds, Julia M. Keogh, Elana Henning & I.
Sadaf Farooqi Life Science Institute, University of Michigan, Ann Arbor, MI, USA Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA I.S.F. has consulted for a number of companies involved in the development of weight loss drugs (Rhythm Pharmaceuticals, Eli Lilly, Sanofi, AstraZeneca, Nodthera, and Novo Nordisk). RDC and the University of Michigan hold equity in Courage Therapeutics, and RDC is a founder and board member of the company. All other authors have no competing interests.
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