Metabolic and neuroendocrine responses to RXFP3 modulation in the central nervous system.
Neuroanatomical studies have shown relaxin-3 neurons, primarily found in the rodent nucleus incertus (NI), project widely into a large number of areas expressing the relaxin-3 receptor (RXFP3), and these data suggest relaxin-3/RXFP3 signaling modulates sensory, emotional, and neuroendocrine processing. The similar distribution of this receptor-ligand pair in the rat, mouse, and monkey brain suggests that experimental findings obtained in lower species will translate to higher species. A role for relaxin-3 and RXFP3 in modulating stress responses is strongly suggested by the expression of corticotropin-releasing factor R1 (CRF-R1) by NI cells, increased relaxin-3 expression in the NI after stress or CRF injection, and hormonal responses to intracerebroventricular (i.c.v.) relaxin-3 injection. Recent data are consistent with a further role for this ligand-receptor pair in modulating memory. In addition, relaxin-3 has been reported to modulate feeding and body weight control. Acute or chronic central (i.c.v. or intraparaventricular) injections of relaxin-3 have shown a consistent stimulatory effect on food consumption while relaxin was inactive, suggesting the phagic effect of relaxin-3 is mediated by RXFP3. We have confirmed the role of RXFP3 in modulating feeding and body weight by using a selective RXFP3 agonist (R3/I5) and antagonist [R3(Delta23-27)R/I5], collecting feeding, body weight, hormone, and body composition data. In addition, we have preliminary body weight and magnetic resonance imaging data from relaxin-3 knockout mice, which on a 129S5:B6 background are smaller and leaner than congenic controls. These data suggest relaxin-3, acting through RXFP3, is involved in coordinating stress, learning and memory, and feeding responses as predicted on the basis of neuroanatomy.
Johnson & Johnson Pharmaceutical Research & Development, LLC, San Diego, California 92121, USA. ssutton@its.jnj.com
Steven W
SW
Sutton
Jonathan
J
Shelton
Craig
C
Smith
John
J
Williams
Sujin
S
Yun
Timothy
T
Motley
Chester
C
Kuei
Pascal
P
Bonaventure
Andrew
A
Gundlach
Changlu
C
Liu
Timothy
T
Lovenberg
D000821:Animal Feed; D000818:Animals; D001835:Body Weight; D002490:Central Nervous System / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012065:Relaxin / Q000235:genetics / Q000494:pharmacology / Q000502:physiology
D043562:Receptors, G-Protein-Coupled; D012065:Relaxin