Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin- and melanocortin-3 receptors

Rediger, Anne; Piechowski, CL; Yi, CX; Tarnow, Patrick; Strotmann, Rainer; Grüters, Annette; Krude, Heiko; Schöneberg, Torsten; Tschöp, MH; Kleinau, Gunnar; Biebermann, Heike

doi:10.1055/s-0032-1330075

Cited by 8 publications

(10 citation statements)

References 20 publications

(22 reference statements)

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“…GHSR-1A has been shown to heterodimerise with the melanocortin 3 receptor, the serotonin 2C receptor and the dopamine receptors, which are all involved in food intake and food reward regulation. Heterodimerisation could serve to modulate specific functions of GHSR-1A, such as signalling pathways, or to act as an allosteric mechanism to regulate signalling pathways of the other receptors, independently of ghrelin binding (141)(142)(143)(144).…”

Section: Physiological Role Of the Ghrelin Signalling System On Food mentioning

confidence: 99%

Ghrelin Signalling on Food Reward: A Salient Link Between the Gut and the Mesolimbic System

Perelló

Dickson

2015

J Neuroendocrinology

139

117

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.'Hunger is the best spice' is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry. The neurobiological underpinnings of this lore include activation of the brain's reward system and the stimulation of this system by the hunger-promoting hormone ghrelin. Ghrelin is produced largely from the stomach and levels are higher preprandially. The ghrelin receptor is expressed in many brain areas important for feeding control, including not only the hypothalamic nuclei involved in energy balance regulation, but also reward-linked areas such as the ventral tegmental area. By targeting the mesoaccumbal dopamine neurones of the ventral tegmental area, ghrelin recruits pathways important for food reward-related behaviours that show overlap with but are also distinct from those important for food intake. We review a variety of studies that support the notion that ghrelin signalling at the level of the mesolimbic system is one of the key molecular substrates that provides a physiological signal connecting gut and reward pathways.

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Section: Physiological Role Of the Ghrelin Signalling System On Food mentioning

confidence: 99%

Ghrelin Signalling on Food Reward: A Salient Link Between the Gut and the Mesolimbic System

Perelló

Dickson

2015

J Neuroendocrinology

139

117

View full text Add to dashboard Cite

show abstract

“…Ghrelin is linked to emotion-mediated food intake involving both D1 and D2 receptors in the striatum via the ghrelin receptor (Acquas et al 1989;Overduin et al 2012;Richard & Berridge 2011). Furthermore, recent studies show that ghrelin receptor can promiscuously heterodimerize with melanocortin3 receptor (MC 3 R), D1R, D2R and 5HT 2C R that can alter ghrelin signaling in vitro and specifically heterodimerization with non-edited 5HT 2C R can attenuate ghrelin signaling (Kern et al 2012;Rediger et al 2011). Thus, dysregulated dopamine receptors and 5HT 2C R in hypothalamus may be interacting with ghrelin receptor and altering feeding behavior of ADAR2 transgenic mice.…”

Section: Discussionmentioning

confidence: 99%

Hyperactive hypothalamus, motivated and non‐distractible chronic overeating in ADAR2 transgenic mice

Akubuiro¹,

Zimmerman²,

Ponto³

et al. 2013

Genes Brain and Behavior

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ADAR2 transgenic mice misexpressing the RNA editing enzyme ADAR2 (Adenosine Deaminase that act on RNA) show characteristics of overeating and experience adult onset obesity. Behavioral patterns and brain changes related to a possible addictive overeating in these transgenic mice were explored as transgenic mice display chronic hyperphagia. ADAR2 transgenic mice were assessed in their food preference and motivation to overeat in a competing reward environment with ad lib access to a running wheel and food. Metabolic activity of brain and peripheral tissue were assessed with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and RNA expression of feeding related genes, ADAR2, dopamine and opiate receptors from the hypothalamus and striatum were examined. The results indicate that ADAR2 transgenic mice exhibit, (1) a food preference for diets with higher fat content, (2) significantly increased food intake that is non-distractible in a competing reward environment, (3) significantly increased mRNA expressions of ADAR2, serotonin 2C receptor (5HT2CR), D1, D2, and mu opioid receptors and no change in CRH mRNAs and significantly reduced ADAR2 protein expression in the hypothalamus, (4) significantly increased D1 receptor and altered bioamines with no change in ADAR2, mu opioid and D2 receptor mRNA expression in the striatum, and (5) significantly greater glucose metabolism in the hypothalamus, brain stem, right hippocampus, left and right mid brain regions and suprascapular peripheral tissue than controls. These results suggest that highly motivated and goal-oriented overeating behaviors of ADAR2 transgenic mice are associated with altered feeding, reward-related mRNAs, and hyperactive brain mesolimbic region.

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“…Alternatively, there may be an as yet undiscovered endogenous ligand, acting as a receptor agonist, or as an inverse agonist (Zigman et al, 2006) that modulates the constitutive activity of GHSR (Holst et al, 2003). A role for constitutive activity is suggested by the finding that the basal activity of GHSR enhances the signaling efficiency of the MC3R, which is coexpressed with GHSR in neurons in the arcuate nucleus and that unmodified substance P can act as an inverse agonist of GHSR (Rediger et al, 2011). Furthermore, the constitutive GHSR signal may be regulated by alteration of the expression levels of the receptor.…”

Section: Ghsr Signaling In the Brain In The Absence Of Ghrelinmentioning

confidence: 99%

Expression of the ghrelin receptor gene in neurons of the medulla oblongata of the rat

Bron

Yin

Russo

et al. 2013

J of Comparative Neurology

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There is ambiguity concerning the distribution of neurons that express the ghrelin receptor (GHSR) in the medulla oblongata. In the current study we used a sensitive nonradioactive method to investigate GHSR mRNA distribution by in situ hybridization. Strong expression of the GHSR gene was confirmed in neurons of the facial nucleus (FacN, 7), the dorsal vagal complex (DVC), and the semicompact (but not compact) nucleus ambiguus (AmbSC and AmbC). In addition, expression of GHSR was found in other regions, where it had not been described before. GHSR-positive neurons were observed in the gustatory rostral nucleus tractus solitarius and in areas involved in vestibulo-ocular processing (such as the medial vestibular nucleus and the nucleus abducens). GHSR expression was also noted in ventral areas associated with cardiorespiratory control, including the gigantocellular reticular nucleus, the lateral paragigantocellular nucleus, the rostral and caudal ventrolateral medulla, the (pre)-Bötzinger complex, and the rostral and caudal ventrolateral respiratory group. However, GHSR-positive neurons in ventrolateral areas did not express markers for cardiovascular presympathetic vasomotor neurons, respiratory propriobulbar rhythmogenic neurons, or sensory interneurons. GHSR-positive cells were intermingled with catecholamine neurons in the dorsal vagal complex but these populations did not overlap. Thus, the ghrelin receptor occurs in the medulla oblongata in 1) second-order sensory neurons processing gustatory, vestibulo-ocular, and visceral sensation; 2) cholinergic somatomotor neurons of the FacN and autonomic preganglionic neurons of the DMNX and AmbSC; 3) cardiovascular neurons in the DVC, Gi, and LPGi; 4) neurons of as yet unknown function in the ventrolateral medulla.

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Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin- and melanocortin-3 receptors

Cited by 8 publications

References 20 publications

Ghrelin Signalling on Food Reward: A Salient Link Between the Gut and the Mesolimbic System

Ghrelin Signalling on Food Reward: A Salient Link Between the Gut and the Mesolimbic System

Hyperactive hypothalamus, motivated and non‐distractible chronic overeating in ADAR2 transgenic mice

Expression of the ghrelin receptor gene in neurons of the medulla oblongata of the rat

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