Serotonin Reciprocally Regulates Melanocortin Neurons to Modulate Food Intake

Abstract

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

Serotonin controlling feeding and satiety

“…In conclusion, it appears that both 5-HT2C and 5-HTB receptors are involved in arcuate control of feeding, where they act via different, but complementary mechanisms [170]. In the light of the discussion of possible 5-HT and leptin interactions in satiety it is important to mention that leptin and 5-HT are activating distinct POMC neurons in the arcuate nucleus [171], further supporting the view that there is no direct interaction between 5-HT and leptin at the neuronal level.…”

“…There is recent evidence that 5-HT1B receptors inhibit the activity of NPY/AgRP neurons in the arcuate nucleus [170,171]. In conclusion, it appears that both 5-HT2C and 5-HTB receptors are involved in arcuate control of feeding, where they act via different, but complementary mechanisms [170].…”

Palatability Can Drive Feeding Independent of AgRP Neurons

“…5-HT innervation of ARC neurons mediates satiety by the concerted activation of both the Gi-coupled 5-HT 1B receptors on AgRP neurons and Gq-coupled 5-HT 2C receptor activation on POMC neurons (Heisler et al, 2006). This arrangement predicts that AgRP-ablated mice should manifest reduced sensitivity to the anorectic effects of 5HT 1B R compared to the 5HT 2C R agonist.…”

“…This arrangement predicts that AgRP-ablated mice should manifest reduced sensitivity to the anorectic effects of 5HT 1B R compared to the 5HT 2C R agonist. Feeding response after a fast on a chow diet was monitored following administration of the selective 5-HT 1B R agonist CP94253 (CP) and 5-HT 2C R agonist WAY161503 (WAY) using doses that produce significant reduction in refeeding (Heisler et al, 2006). While pretreatment with CP 45 min prior to refeeding produced a ~50% decrease in chow intake in control animals, this treatment was ineffective compared to saline in mice lacking AgRP neurons ( Figure 5A, 5B).…”

“…Serotonin (5-hydroxytryptamine, 5-HT) is known to have anorexic properties and serotonergic drugs have been widely used as anti-obesity treatments (Lam and Heisler, 2007). Serotonergic innervation of ARC neurons mediates the satiety action of serotonin through the concerted activation of POMC neurons and inhibition of AgRP neurons (Heisler et al, 2006). Administration of ghrelin, a stomach-derived 28 amino-acid peptide, in both humans and rodents was shown to increase food intake through the binding to the growth hormone secretagogue receptor 1 (GHS-R) (Kojima et al, 1999).…”