Review
Brain serotonin system in the coordination of food intake and body weight

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Abstract

An inverse relationship between brain serotonin and food intake and body weight has been known for more than 30 years. Specifically, augmentation of brain serotonin inhibits food intake, while depletion of brain serotonin promotes hyperphagia and weight gain. Through the decades, serotonin receptors have been identified and their function in the serotonergic regulation of food intake clarified. Recent refined genetic studies now indicate that a primary mechanism through which serotonin influences appetite and body weight is via serotonin 2C receptor (5-HT2CR) and serotonin 1B receptor (5-HT1BR) influencing the activity of endogenous melanocortin receptor agonists and antagonists at the melanocortin 4 receptor (MC4R). However, other mechanisms are also possible and the challenge of future research is to delineate them in the complete elucidation of the complex neurocircuitry underlying the serotonergic control of appetite and body weight.

Research Highlights

► Serotonergic tone is inversely correlated with food intake. ► Distinct serotonin receptors exert effects on appetite. ► Multiple brain effector pathways mediate the effects of serotonin on food intake.

Introduction

Serotonin (5-hydroxytryptamine; 5-HT) is a biogenic amine that is synthesized both in the enteric nervous system and the central nervous system (CNS). In the CNS, serotonin is released throughout most of the neuraxis and acts as a modulatory neurotransmitter. Perhaps most commonly associated with the regulation of mood and anxiety, brain serotonin also coordinates numerous cognitive, autonomic, and other functions to maintain homeostasis and ensure survival and reproduction. Here we review the modulation of food intake by brain serotonin, discussing: (i) the neuroanatomy and basic function of the brain serotonin system; (ii) the evidence for regulation of food intake by endogenous brain serotonin; and (iii) the current state of understanding of the mechanisms employed by serotonin to affect food intake, focusing on the serotonin receptors and neuronal mediators recruited by serotonin to this end.

Section snippets

Evolution

The presence of serotonin synthesis in plants (Kolar and Machackova, 2005) as well as all branches of metazoan life thus far studied (Hay-Schmidt, 2000, Weiger, 1997) demonstrates that serotonin arose relatively early in the evolution of life. Indeed, the plant–animal evolutionary divergence, which was probably preceded by the evolution of serotonin, is estimated to have occurred 1.5 billion years ago (Wang et al., 1999). Although serotonin appears to function as a trophic factor in plants, its

Manipulations of endogenous serotonin: effects on food intake and body weight

Manipulation of endogenous serotonin synthesis, bioavailability, and metabolism provides important evidence for the role of endogenous serotonin in coordinating food intake and body weight. Collectively, these data illustrate the inverse relationship between the level of brain serotonin signaling and food intake — when brain serotonin signaling is augmented, food intake is reduced, and vice versa. Numerous genetic models of serotonin receptor deficiency, tryptophan hydroxylase deficiency, and

5-HT1R family

The inhibitory 5-HT1Rs, in their role as autoreceptors, permit feedback inhibition of serotonin neurons by serotonin. The 5-HT1AR subtype is found both on the cell soma and postsynaptically, whereas the 5-HT1BR is primarily expressed on terminals, but is also postsynaptically expressed. Application of 5-HT1AR agonists to dorsal and median raphe slices reduces serotonin release (Hopwood and Stamford, 2001), while application of a 5-HT1BR agonist to the hippocampus, a target of 5-HT innervation,

Integration of the serotonin systems with brain pathways modulating food intake and body weight

Food intake is controlled by a complex combination of responses in the brain. The brainstem has been reported to mediate reflex satiety responses involving the sensing of short-term fluctuations in nutritional state causing the initiation of appropriate gastrointestinal and motor responses. Hypothalamic centres have been reported to integrate information about long-term energy stores and other physiological and environmental factors to formulate appropriate feeding responses. The motivational

Summary

Based on extensive genetic and pharmacological evidence, serotonin plays an important role in the control of food intake and, consequentially, body weight. The serotonin system is relatively complex in terms of anatomical projections, receptor subtypes, and its breadth of functional roles. Nevertheless, ongoing research continues to delineate the brain pathways underlying the regulation of food intake and body weight by brain serotonin. Much remains to be understood about the serotonin

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