Central Relaxin-3 Administration Causes Hyperphagia in Male Wistar Rats

McGowan, Barbara; Stanley, Sarah A.; Smith, Kirk P.; White, N. E.; Connolly, Maya; Thompson, Emily L.; Gardiner, James; Murphy, Kevin G.; Ghatei, Mohammed A.; Bloom, Stephen R.

doi:10.1210/en.2004-1532

Cited by 168 publications

(250 citation statements)

References 26 publications

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“…Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels of RXFP3 (11,15,(17)(18)(19)(20)(21)(22). This pattern of innervation, along with findings that relaxin-3 can modulate (i) food intake (23)(24)(25), (ii) responses to stress (20,26,27), (iii) arousal (28,29), and (iv) interactions with the corticotropin-releasing factor (CRF) systems (20,26), led us to hypothesize that relaxin-3 may modulate aspects of behavior related to substance use and abuse. Such a role would parallel that of other neuropeptides, such as orexin/hypocretin (30,31), galanin (32), and melanin-concentrating hormone (33).…”

Section: Addiction | Dependencementioning

confidence: 80%

Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

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Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased selfadministration of alcohol in a dose-related manner and attenuated cue-and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/ RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of rewardseeking. addiction | dependenceA lcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed "alcohol addiction") (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6-8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7-10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11-16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels ...

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Section: Addiction | Dependencementioning

confidence: 80%

Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

114

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“…We have recently shown for the first time, that acute intracerebroventricular and iPVN administration of low dose H3 stimulates feeding in satiated male Wistar rats in the early light phase [12]. The lowest dose of H3 to elicit a significant orexigenic response when administered iPVN was seen in the picomolar range at 18 pmol, similar to other orexigenic peptides such as ghrelin and NPY.…”

Section: Introductionmentioning

confidence: 78%

“…We have recently demonstrated that relaxin-3 may play a role in the regulation of food intake [12]. The aim of the current study was to investigate the maximum orexigenic response elicited by H3.…”

Section: Discussionmentioning

confidence: 96%

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Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats

McGowan

Stanley

Smith

et al. 2006

Regulatory Peptides

118

158

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The effects of acute and repeated intraparaventricular (iPVN) administration of human relaxin-3 (H3) were examined on food intake, energy expenditure, and the hypothalamic-pituitary thyroid axis in male Wistar rats. An acute high dose iPVN injection of H3 significantly increased food intake 1 hour post-administration [0.4 ± 0.1g (vehicle) vs 1.6 ± 0.5g (180pmol H3), 2.4 ± 0.5g (540pmol H3) and 2.2 ± 0.5g (1620pmol H3), p< 0.05 for all doses vs vehicle]. Repeated iPVN H3 injection (180pmol/twice a day for 7 days) significantly increased cumulative food intake in ad libitum fed animals compared with vehicle [211.8 ± 7.1g (vehicle) vs 261.6 ± 6.7g (ad libitum fed H3), p< 0.05]. Plasma leptin was increased in the H3 ad libitum fed group. Plasma thyroid stimulating hormone was significantly decreased after acute and repeated administration of H3. These data suggest H3 may play a role in longterm control of food intake.

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“…Relaxin-3 and its receptor GPCR135 are both predominantly expressed in the brain (11,14), in particular in regions dealing with sensory signals (15,16). This finding, together with recent in vivo studies that revealed that relaxin-3 is involved in stress responses (17) and in regulation of feeding (18), suggest a physiological role in neuroendocrine and sensory processing. An interesting feature of relaxin-3 is its ability to activate both GPCR142 (19) and LGR7 (20) in addition to its own receptor, GPCR135 (11).…”

mentioning

confidence: 75%

Structure of the R3/I5 Chimeric Relaxin Peptide, a Selective GPCR135 and GPCR142 Agonist

Haugaard‐Jönsson¹,

Hossain

Daly

et al. 2008

Journal of Biological Chemistry

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The human relaxin family comprises seven peptide hormones with various biological functions mediated through interactions with G-protein-coupled receptors. Interestingly, among the hitherto characterized receptors there is no absolute selectivity toward their primary ligand. The most striking example of this is the relaxin family ancestor, relaxin-3, which is an agonist for three of the four currently known relaxin receptors: GPCR135, GPCR142, and LGR7. Relaxin-3 and its endogenous receptor GPCR135 are both expressed predominantly in the brain and have been linked to regulation of stress and feeding. However, to fully understand the role of relaxin-3 in neurological signaling, the development of selective GPCR135 agonists and antagonists for in vivo studies is crucial. Recent reports have demonstrated that such selective ligands can be achieved by making chimeric peptides comprising the relaxin-3 B-chain combined with the INSL5 A-chain. To obtain structural insights into the consequences of combining A-and B-chains from different relaxins we have determined the NMR solution structure of a human relaxin-3/INSL5 chimeric peptide. The structure reveals that the INSL5 A-chain adopts a conformation similar to the relaxin-3 A-chain, and thus has the ability to structurally support a native-like conformation of the relaxin-3 B-chain. These findings suggest that the decrease in activity at the LGR7 receptor seen for this peptide is a result of the removal of a secondary LGR7 binding site present in the relaxin-3 A-chain, rather than conformational changes in the primary B-chain receptor binding site.The human relaxin family of peptide hormones comprises seven members in humans, including relaxins 1-3 (1-3), and the insulin-like peptides INSLs 3-6 (4 -7). Relaxin-1 is the result of a gene duplication only present in higher primates and relaxin-2 is the human equivalent of "relaxin" in all other mammals. The relaxins are structurally related to insulin and, together with insulin and the insulin-like growth factors I and II, they make up the insulin/relaxin superfamily (Fig. 1). These peptides share the structural characteristics of two peptide chains, A and B, which comprise around 24 and 30 amino acids, respectively, and are cross-braced by three disulfide bonds (8). Despite being structural relatives of insulin and the insulin-like growth factors, which activate tyrosine kinase receptors, it was recently established that relaxins interact with G-protein-coupled receptors (GPCRs).3 To date four so-called relaxin family peptide receptors (RXFPs) have been characterized and identified as the endogenous receptors of relaxin, INSL3, relaxin-3, and INSL5, namely LGR7 (RXFP1) (9), LGR8 (RXFP2) (10), GPCR135 (RXFP3) (11), and GPCR142 (RXFP4) (12), respectively. Interestingly, despite these receptors interacting with similar ligands, GPCR135 and GPCR142 are of the classic peptide ligand receptor types, whereas LGR7 and LGR8 belong to an unrelated class, which is characterized by a large extracellular leucine-rich repeat containi...

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Central Relaxin-3 Administration Causes Hyperphagia in Male Wistar Rats

Cited by 168 publications

References 26 publications

Relaxin-3/RXFP3 system regulates alcohol-seeking

Relaxin-3/RXFP3 system regulates alcohol-seeking

Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats

Structure of the R3/I5 Chimeric Relaxin Peptide, a Selective GPCR135 and GPCR142 Agonist

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