RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior
- Alan Kania1,3,
- Agata Szlaga1,
- Patryk Sambak1,
- Anna Gugula1,
- Ewa Blasiak2,
- Maria Vittoria Micioni Di Bonaventura3,
- Mohammad Akhter Hossain4,
- Carlo Cifani3,
- Grzegorz Hess1,
- Andrew L. Gundlach4, and
- Anna Blasiak1
- 1Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, 30-387, Poland
- 2Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, 30-387, Poland
- 3School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy
- 4Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, 3010 Victoria, Australia
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Author contributions: A.K., C.C., G.H., A.L.G., and A.B. designed research; A.K., A.S., P.S., A.G., E.B., and M.V.M.D.B. performed research; A.K., A.S., P.S., A.G., E.B., and M.V.M.D.B. analyzed data; A.K. and A.B. wrote the first draft of the paper; A.K., C.C., G.H., A.L.G., and A.B. edited the paper; M.A.H. and A.L.G. contributed unpublished reagents/analytic tools.
Abstract
Binge-eating disorder is the most common eating disorder. Various neuropeptides play important roles in the regulation of feeding behavior, including relaxin-3 (RLN3), which stimulates food intake in rats through the activation of the relaxin-family peptide-3 receptor (RXFP3). Here we demonstrate that a likely mechanism underlying the orexigenic action of RLN3 is RXFP3-mediated inhibition of oxytocin- and arginine-vasopressin-synthesizing paraventricular nucleus (PVN) magnocellular neurosecretory cells. Moreover, we reveal that, in male and female rats, this action depends on M-like potassium conductance. Notably, higher intra- and peri-PVN RLN3 fiber densities were observed in females, which may constitute an anatomic substrate for observed sex differences in binge-eating disorder. Finally, in a model of binge-eating in female rats, RXFP3 blockade within the PVN prevented binge-eating behavior. These data demonstrate a direct RLN3/RXFP3 action in the PVN of male and female rats, identify the associated ionic mechanisms, and reveal that hypothalamic RLN3/RXFP3 signaling regulates binge-eating behavior.
SIGNIFICANCE STATEMENT Binge-eating disorder is the most common eating disorder worldwide, affecting women twice as frequently as men. Various neuropeptides play important roles in the regulation of feeding behavior, including relaxin-3, which acts via the relaxin-family peptide-3 receptor (RXFP3). Using a model of binge-eating, we demonstrated that relaxin-3/RXFP3 signaling in the hypothalamic paraventricular nucleus (PVN) is necessary for the expression of binge-eating behavior in female rats. Moreover, we elucidated the neuronal mechanism of RLN3/RXFP3 signaling in PVN in male and female rats and characterized sex differences in the RLN3 innervation of the PVN. These findings increase our understanding of the brain circuits and neurotransmitters involved in binge-eating disorder pathology and identify RXFP3 as a therapeutic target for binge-like eating disorders.
- Received December 10, 2019.
- Revision received April 17, 2020.
- Accepted May 21, 2020.
- Copyright © 2020 Kania et al.
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