ReviewSerotonergic pathways converge upon central melanocortin systems to regulate energy balance
Section snippets
Leptin-regulated pathways affecting energy balance
The hypothalamus has long been acknowledged as a primary brain region regulating food intake and body weight [14], [15]. Leptin, a hormone produced by adipocytes, was first described a decade ago by Zhang and co-workers and has since been established as one of the key players in the neurobiology of energy balance [13], [14], [15], [16], [53]. The central circuitry required for the metabolic effects of leptin includes melanocortin pathways in the arcuate nucleus of the hypothalamus (Arc).
Mapping serotonergic pathways regulating energy balance
Within the past 30 years, substantial evidence has accumulated supporting an inverse relationship between central serotonin levels and food intake. Specifically, it has been shown that pharmacological agents that enhance central levels of 5-HT suppress food intake, whereas drugs that antagonize the actions of 5-HT increase food intake [46]. Therefore, serotonergic indirect agonists such as d-Fenfluramine (d-Fen), which block the reuptake of serotonin and stimulate its release, have been
Serotonin receptors expressed in the Arc
Serotonin's effects on POMC/α-MSH neuronal activity may be achieved through activation of one or both of the identified Gq-coupled serotonin receptors expressed in the Arc, 5-HT2AR (formerly 5-HT2R) and/or 5-HT2CR (formerly 5-HT1CR) [6], [45]. Based on the distribution pattern of 5-HT2ARs in the Arc, it is likely that these receptors are co-expressed with POMC to some extent, but this remains to be confirmed. Despite this, no reports of disruptions in energy balance have been published in 5-HT2A
Role of melanocortin 4 receptors (MC4R) in energy balance
Activation of POMC neurons increases the release of the endogenous melanocortin receptor agonist α-MSH, which displays a high binding affinity for the MC4R [1]. A recent surge of genetic and pharmacological research implicates MC4Rs as a critical mediator of energy balance [17], [18], [27]. The CNS distribution of MC4R mRNA in the rat and mouse is consistent with a regulatory role in food intake and body weight [31], [33], [36]. A high degree of MC4R mRNA is evident in the PVH and modest
Conclusions
The past decade has seen major advances in the elucidation of the complex neurocircuitry underlying feeding behavior and body weight regulation. The leptin, serotonin and melanocortin signaling systems have been demonstrated to be highly effective in altering food intake and body weight [46], [49], [52], [54]. It appears that these and other metabolic signals converge upon Arc POMC- and AGRP-containing neurons, and thereby downstream MC4Rs, as a common output mechanism to promote energy
References (53)
- et al.
Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis
Neuron
(2004) - et al.
Mouse models of serotonin receptor function: toward a genetic dissection of serotonin systems
Pharmacol Ther
(2000) - et al.
The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis
Neuron
(2003) - et al.
Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area
Neuron
(1999) - et al.
From lesions to leptin: hypothalamic control of food intake and body weight
Neuron
(1999) - et al.
Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands
Brain Res
(1998) - et al.
The neuroanatomical axis for control of energy balance
Front Neuroendocrinol
(2002) Clinical studies with d-fenfluramine
Am J Clin Nutr
(1992)- et al.
Acute and chronic fluoxetine attenuates fat and protein but not carbohydrate consumption in female rats
Pharmacol, Biochem Behav
(1999) - et al.
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
Cell
(1997)