Ghrelińs Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction

Abstract

Understanding the intricate pathways that modulate appetite and subsequent food intake is of particular importance considering the rise in the incidence of obesity across the globe. The serotonergic system, specifically the 5-HT 2C receptor, has been shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor that is well-known 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-HT 2C 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-HT 2C dimer-induced attenuation of calcium signaling is not due to coupling to Gα S, as no increase in cAMP signaling is observed. Next, flow cytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT 2C receptor. In addition, we demonstrate colocalized expression of the 5-HT 2C 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-HT 2C receptor signaling is blocked ghreliņs orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT 2C 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-HT 2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT 2C receptor interaction translates into a biologically significant modulation of ghreliņs orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT 2C receptor treatment strategy in weight management.