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.
Highlights
Relaxin-3 (RLN3) is a neuropeptide expressed mainly in neurons of the brainstem nucleus incertus (NI)
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
RLN3/RXFP3 signaling inhibits a majority of PVN Magnocellular neurosecretory cells (MNCs) in male and female rats In a series of whole-cell recordings ex vivo, we investigated the effects of RLN3 and a selective, high-affinity RXFP3 agonist peptide on the electrophysiology of PVN MNCs in male and female Sprague Dawley rats, and explored possible sex differences in recorded responses
Summary
Relaxin-3 (RLN3) is a neuropeptide expressed mainly in neurons of the brainstem nucleus incertus (NI). Smaller assemblies of RLN3 neurons are scattered within the pontine raphe nucleus (PnR), an area dorsal to the substantia nigra (dSN), and in the medial/ventral periaqueductal gray (PAG). The cognate metabotropic receptor for RLN3, relaxin-family peptide 3 receptor. 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. (RXFP3) couples to Gi/o-proteins and is widely expressed in the CNS (for review, see Bathgate et al, 2013). RLN3/RXFP3 signaling plays an important role in the control of food intake, arousal and motivation, contextual and spatial
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