A ghrelin receptor and oxytocin receptor heterocomplex impairs oxytocin mediated signalling

Fitzsimons, Shauna E. Wallace; Chruścicka, Barbara; Druelle, Clémentine; Stamou, Panagiota; Nally, Ken; Dinan, Timothy G.; Cryan, John F.; Schellekens, Harriët

doi:10.1016/j.neuropharm.2018.12.022

Cited by 40 publications

(38 citation statements)

References 113 publications

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“…The extent to which circulating OT may inhibit food intake through suppression of the orexigenic signal, ghrelin, is controversial. It has been reported that ghrelin administration centrally can stimulate OT release in rodents ( Szabo et al, 2019 ) and heterocomplex formed by OT receptor and ghrelin receptor can alter OT signaling ( Wallace Fitzsimons et al, 2019 ) (see section “Mechanism of Action Following Peripheral Administration”). One study reported that peripheral OT treatment decreased circulating levels of ghrelin in men ( Vila et al, 2009 ) during a time that is consistent with when OT reduces food intake in rodents ( Ho et al, 2014 ).…”

Section: Mechanism Of Action Following Peripheral Administrationmentioning

confidence: 99%

“…Given that the OTR is a GPCR it is prone to the formation of heterodimers with other GPCRs that are in close proximity. These heterodimers can impact intracellular signaling pathways, allosteric interactions, endocytosis, biological function and drug effects ( Schellekens et al, 2013 ; Wallace Fitzsimons et al, 2019 ). This is of particular interest given that OT and ghrelin have opposing actions on food intake and OTRs and the growth hormone secretagogue receptor (GHS-R1a) have overlapping areas of expression in many CNS sites linked to the control of food intake and/or energy expenditure (including the ARC, VMH, NTS, and VTA) ( Abizaid et al, 2006 ; Zigman et al, 2006 ).…”

Section: Oxytocin Receptor Dimerizationmentioning

confidence: 99%

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Oxytocin as an Anti-obesity Treatment

2021

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Obesity is a growing health concern, as it increases risk for heart disease, hypertension, type 2 diabetes, cancer, COVID-19 related hospitalizations and mortality. However, current weight loss therapies are often associated with psychiatric or cardiovascular side effects or poor tolerability that limit their long-term use. The hypothalamic neuropeptide, oxytocin (OT), mediates a wide range of physiologic actions, which include reproductive behavior, formation of prosocial behaviors and control of body weight. We and others have shown that OT circumvents leptin resistance and elicits weight loss in diet-induced obese rodents and non-human primates by reducing both food intake and increasing energy expenditure (EE). Chronic intranasal OT also elicits promising effects on weight loss in obese humans. This review evaluates the potential use of OT as a therapeutic strategy to treat obesity in rodents, non-human primates, and humans, and identifies potential mechanisms that mediate this effect.

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Section: Mechanism Of Action Following Peripheral Administrationmentioning

confidence: 99%

Section: Oxytocin Receptor Dimerizationmentioning

confidence: 99%

Oxytocin as an Anti-obesity Treatment

2021

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“…It is very likely that the function of the ghrelin/GHSR system is not solely dependent on the binding of AG to its receptor, but that also changes in GHSR expression levels might have pervasive biological effects. Furthermore, there is evidence that the GHSR can form heterodimers with various other receptors like for example those for dopamine, serotonin or oxytocin (Schellekens et al, 2013b;Kern et al, 2015;Wallace Fitzsimons et al, 2019), which affects downstream signaling and receptor trafficking (for review see Schellekens et al, 2013a;Abizaid and Hougland, 2020). Recent findings also suggest that the liverexpressed antimicrobial peptide 2 (LEAP2) acts as an endogenous antagonist/inverse agonist of the GHSR that modulates ghrelin function in response to the feeding status (Ge et al, 2018).…”

Section: Ghrelin Receptors (Ghsr)mentioning

confidence: 99%

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

Fritz

Singewald

Bundel

2020

Front. Synaptic Neurosci.

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Ghrelin is a peptide hormone released by specialized X/A cells in the stomach and activated by acylation. Following its secretion, it binds to ghrelin receptors in the periphery to regulate energy balance, but it also acts on the central nervous system where it induces a potent orexigenic effect. Several types of stressors have been shown to stimulate ghrelin release in rodents, including nutritional stressors like food deprivation, but also physical and psychological stressors such as foot shocks, social defeat, forced immobilization or chronic unpredictable mild stress. The mechanism through which these stressors drive ghrelin release from the stomach lining remains unknown and, to date, the resulting consequences of ghrelin release for stress coping remain poorly understood. Indeed, ghrelin has been proposed to act as a stress hormone that reduces fear, anxiety-and depression-like behaviors in rodents but some studies suggest that ghrelin may-in contrast-promote such behaviors. In this review, we aim to provide a comprehensive overview of the literature on the role of the ghrelin system in stress coping. We discuss whether ghrelin release is more than a byproduct of disrupted energy homeostasis following stress exposure. Furthermore, we explore the notion that ghrelin receptor signaling in the brain may have effects independent of circulating ghrelin and in what way this might influence stress coping in rodents. Finally, we examine how the ghrelin system could be utilized as a therapeutic avenue in stressrelated psychiatric disorders (with a focus on anxiety-and trauma-related disorders), for example to develop novel biomarkers for a better diagnosis or new interventions to tackle relapse or treatment resistance in patients.

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“…However, dimerization is thought to occur in the absence of ghrelin, indicating allosteric regulatory processes 39 (figure 2). GHS-R1a has also been shown to modulate serotonin signalling via dimerization with 5-HT2C receptors 40,41 and oxytocin receptors 42 , whilst GHS-R1b forms heterodimers with GHS-R1a to diminish cell surface expression 32,43 . To add further complexity, GHS-R1a exhibits high constitutive activity, at least in-vitro [44][45][46] .…”

Section: Ghrelinmentioning

confidence: 99%

Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease

Buntwal

Sassi

Morgan

et al. 2019

Trends in Endocrinology & Metabolism

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Acyl-ghrelin (AG): A Form of ghrelin that has been acylated by GOAT, which enables it to bind to GHS-R1a. Acyl-protein thioesterase 1 (APT1): An endogenous enzyme known to de-acylate acylghrelin Allosteric mechanism: Regulation of a protein or receptor independent of its active site. Brain derived neurotrophic factor (BDNF): A growth factor in the brain, involved in cell proliferation, survival, learning and memory. Bromodeoxyuridine (BrdU): A synthetic thymidine analogue, incorporated into DNA during replication. It can be used as a marker of proliferation during a specific timeframe. Butyrylcholinesterase: An enzyme that hydrolyses many different choline-based esters, but can also de-acylate acyl-ghrelin, (AG) to form unacylated ghrelin (UAG). Endogenous esterase enzyme present in the plasma known to de-acylate acyl-ghrelin. Caloric restriction (CR): A reduction of food intake (typically 30% less) in the absence of malnutrition. Calorie Restriction mimetics: endogenous or exogenous factors that mimic the effects of CR cAMP response element binding protein (CREB): A transcription factor regulating BDNF expression and important in neuronal plasticity and memory. Dentate gyrus (DG): A sub-region of the hippocampus where neurogenesis occurs. Ghrelin-O-Acyl transferase (GOAT): a member of the membrane bound O-Acyl transferase (MBOAT) family, the only enzyme known to acylate ghrelin. GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR) receptors: Glutamate receptor and ion channels responsible for fast excitatory synaptic transmission. Important for synaptic plasticity and long-term potentiation (LTP). Growth hormone secretagogue receptor (GHSR): A G-protein-coupled receptor (GPCR) also known as the ghrelin receptor. It is the only known receptor for acyl-ghrelin. GHSR-eGFP mice: genetically mutated mice that co-express green fluorescent protein (GFP) with the Growth Hormone Secretagogue Receptor (GHS-R) gene Heterodimers: A protein complex, consisting of two different proteins. Hormesis: A bi-phasic dose-response to a drug or intervention, in which a low dose produces a beneficial effect and a high dose produces a harmful effect. Long-term potentiation (LTP): An important process in memory formation, resulting in a long-term increase in the strength of electrical activity or transmission between two neurones. Neural stem progenitor cells (NSPCs): Multipotent stem cells that reside in the brain with the capacity to differentiate into any neural cell type. Novel object recognition (NOR): Behaviour test of cognitive function that requires recognising novel from familiar objects. This is a hippocampal-dependent task. Passive avoidance learning (PAL): Behaviour test that evaluate memory and learning in rodents with neurological disorders. The rodents learn to avoid an environment in which an aversive stimulus was previously delivered. Pattern separation: The ability to distinguish similar inputs into separate discrete outputs. SAMP8 mice: a naturally occurring mouse model of accelerated ageing wi...

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A ghrelin receptor and oxytocin receptor heterocomplex impairs oxytocin mediated signalling

Cited by 40 publications

References 113 publications

Oxytocin as an Anti-obesity Treatment

Oxytocin as an Anti-obesity Treatment

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

Ghrelin-Mediated Hippocampal Neurogenesis: Implications for Health and Disease

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