Ghrelin’s Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Abstract

Understanding the intricate pathways modulating appetite and subsequent food intake is of particular importance considering the rise in obesity incidence across the globe. The serotonergic system, specifically the 5-HT2C receptor, has shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor wellknown for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signalling is not due to coupling to GαS, as no increase in cAMP signalling is observed. Next, flowcytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor.In addition, we demonstrate co-localized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic-and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signalling is blocked, ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into biological significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management. ACS Paragon Plus Environment ACS Chemical Neuroscience 5

A Novel Non-Peptidic Agonist of the Ghrelin Receptor with Orexigenic Activity In vivo

“…up to 6 hours), following intraperitoneal injection of the 2-pyridone, is promising for the development of treatments for eating and metabolic disorders in humans. This is in sharp contrast to the native peptide ghrelin, which has an initial orexigenic effect, following acute peritoneal administration, which tends to tapers off (relative to vehicle) after 2 hours41 (and SI, Figure S6), most likely due to its short half-life, and thus restricted efficacy in patients.…”

“…Mice underwent habituation to experimental conditions over three consecutive days prior to experimentation in which they were single housed for up to 4 hours following intraperitoneal injection of saline (0.9% NaCl). Following this cumulative food intake studies, with eight animals per group, were performed based on protocols described in previous studies4150. Briefly, on the day of experimentation animals were single housed for 30 minutes without access to food or water.…”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…The complexity of the 5-HT 2CR is even greater than just expected from RNA editing and splicing: 5-HT2CR are able to form homodimers that seem necessary for signal transduction and heteromers with e.g. NMDA or melatonin or ghrelin receptors (HerrickDavis 2013;Herrick-Davis et al 2004;Herrick-Davis and Farrington 2011;Bigford et al 2012;Kamal et al 2015;Schellekens et al 2015). The latter raise further questions about the actual target of drugs such as agomelatine or lorcaserin and their effects in depression or eating behaviour.…”

“…Further, the two receptors colocalize in cultured primary rat hypothalamic and hippocampal neurons (Schellekens et al, 2015). Interestingly, activation and blockade of 5-HT2CR in vivo attenuated and potentiated, respectively, the orexigenic effects of ghrelin.…”

Role of AA-NAT and TPH1 in the Ghrelin-Dependent Regulation of Melatonin Secretion in Sheep during Different Seasons: An <em>In Vitro</em> Study

“…Moreover, in studies by Schellekens et al [33,34], a novel heterodimer involving GHSR-1a and the 5-HT receptor 5-HT2C was identified in the hypothalamus and hippocampus. Moreover, experiments on rodents [35] and ruminants [36] have shown that 5-HT2C and/or 5-HT2B receptors are directly involved in regulating MEL biosynthesis and secretion.…”