Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 21 S6.4

SFEBES2009 Symposia Fit or fat? Mechanisms regulating our metabolic fate (4 abstracts)

Mechanisms of serotonin regulating food intake: the role of the melanocortin pathway

Lora Heisler & Daniel Lam


University of Cambridge, Cambridge, UK.


The central serotonin (5-hydroxytryptamine, 5-HT) system is an established modulator of energy balance. Therefore, it is unsurprising that former (e.g. D-fenfluramine), current (e.g. sibutramine), and drug discovery (e.g. lorcaserin) obesity treatments target serotonin pathways to affect food intake and body weight. Pharmacological and genetic research implicates the Gq-coupled serotonin 2C receptor (5-HT2CR) and the Gi-coupled serotonin 1B receptor (5-HT1BR) specifically in these effects. We sought to clarify how serotonin in general, and the 5-HT2CRs and 5-HT1BRs in particular, modulate ingestive behavior. Through a combination of functional neuroanatomy, genetic, feeding, and electrophysiology studies in rodents, we found that 5-HT2CR and 5-HT1BR agonists require melanocortin pathways to exert their effects on appetite. Specifically, we observed that serotonin and 5-HT2CR agonists activate neurons expressing the endogenous anorectic melanocortin agonist proopiomelanocortin (POMC)/α-melanocyte stimulating hormone (α-MSH) and that serotonin and 5-HT1BR agonists inhibit the activity of neurons expressing the endogenous orexigenic melanocortin antagonist agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. We further verified the necessity for 5-HT2CRs expressed on POMC neurons in serotonin’s effects on energy balance using a genetic mouse line in which 5-HT2CRs are exclusively expressed in POMC neurons. Exclusive expression of 5-HT2CR on POMC neurons abolished the hyperphagia, obesity, and attenuated anorectic responses to serotonergic drugs evident in the complete 5-HT2CR knockout, illustrating that 5-HT2CRs specifically on POMC neurons underlie the effects of 5-HT2CR agonists on energy balance. In the brain, α-MSH and AgRP compete for action at the melanocortin 3 (MC3) and melanocortin 4 (MC4) receptors. To further clarify the pathway through which serotonin influences appetite, we examined whether pharmacological blockade or genetic inactivation of the MC3Rs or MC4Rs abolishes D-fenfluramine, 5-HT2CR and/or 5-HT1BR agonist hypophagia. We observed that activation of the MC4Rs, but not the MC3Rs, is required for D-fenfluramine, 5-HT2CR and 5-HT1BR agonists to influence feeding. A model is presented in which activation of the melanocortin system is downstream of serotonin and is necessary to produce the complete anorectic effect of serotonergic compounds.

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