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

Area of Science:

• Neuroscience
• Endocrinology
• Pharmacology

Background:

• Obesity is a growing global health concern, necessitating research into appetite regulation.
• The 5-HT2C receptor and GHS-R1a receptor are crucial in controlling appetite and energy balance.
• Previous in vitro studies suggested an interaction between these two key receptors.

Purpose of the Study:

• To investigate the functional interaction between the GHS-R1a receptor and the 5-HT2C receptor.
• To confirm the direct physical interaction between GHS-R1a and 5-HT2C receptors.
• To assess the physiological relevance of this interaction in modulating appetite.

Main Methods:

• Utilized cell lines expressing both GHS-R1a and 5-HT2C receptors to study signaling pathways.
• Employed flow cytometry fluorescence resonance energy transfer (fcFRET) to demonstrate direct receptor interaction.
• Examined receptor colocalization in primary rat neurons from the hypothalamus and hippocampus.
• Conducted in vivo studies in rats to assess the effects of receptor modulation on ghrelin-induced feeding.

Main Results:

• The GHS-R1a/5-HT2C dimer interaction does not involve GαS coupling or increased cAMP signaling.
• fcFRET confirmed a direct physical interaction between GHS-R1a and 5-HT2C receptors.
• Both receptors were found to be colocalized in hypothalamic and hippocampal neurons.
• Blocking 5-HT2C receptor signaling potentiated ghrelin's orexigenic effect in vivo.
• The 5-HT2C receptor agonist lorcaserin attenuated ghrelin-induced food intake.

Conclusions:

• The interaction between GHS-R1a and 5-HT2C receptors is biologically significant and directly modulates ghrelin's appetite-stimulating effects.
• This interaction offers a potential therapeutic target for weight management strategies.
• Combined targeting of GHS-R1a and 5-HT2C receptors may represent a novel approach for obesity treatment.