Abstract
The 5-hydroxytryptamine 2C receptor (5-HTR2C) is a class G protein-coupled receptor (GPCR) enriched in the hypothalamus and the brain stem, where it has been shown to regulate energy homeostasis, including feeding and glucose metabolism. Accordingly, 5-HTR2C has been the target of several anti-obesity drugs, though the associated side effects greatly curbed their clinical applications. Dissecting the specific neural circuits of 5-HTR2C-expressing neurons and the detailed molecular pathways of 5-HTR2C signaling in metabolic regulation will help to develop better therapeutic strategies towards metabolic disorders. In this review, we introduced the regulatory role of 5-HTR2C in feeding behavior and glucose metabolism, with particular focus on the molecular pathways, neural network, and its interaction with other metabolic hormones, such as leptin, ghrelin, insulin, and estrogens. Moreover, the latest progress in the clinical research on 5-HTR2C agonists was also discussed.
Highlights
Serotonin, or 5-hydroxytryptamine (5-HT), is an essential neurotransmitter that has been shown to be involved in the regulation of multiple physiological and behavioral functions, including emotion, cognition, sleep, exercise, and energy homeostasis [1, 2]
The role of 5-hydroxytryptamine 2C receptor (5-HTR2C) in POMC neurons and the new role in neural circuits suggest that the new anti-obesity drugs act directly on the central nervous system (CNS), thereby reducing the negative effects caused by acting on the periphery, which will be discussed in the future
The action of CNS 5-HTR2C neuron contributes to the regulation of energy homeostasis and have greatly advanced the understanding of the physiology and behavioral functions of 5-HTR2C in the brain
Summary
5-hydroxytryptamine (5-HT), is an essential neurotransmitter that has been shown to be involved in the regulation of multiple physiological and behavioral functions, including emotion, cognition, sleep, exercise, and energy homeostasis [1, 2]. Mice with global mutation or knock-out of the 5HTR2C gene (2C-null) developed hyperphagia and obesity (Table 1) [5, 25, 26], and 5-HTR2C agonist d-Fen was reported to suppress mice food intake, contributing to the anorexigenic effects [27]. Electrophysiological studies showed that selective 5-HTR2C agonists, including m-chlorophenyl piperazine (mCPP), d-Fen [23], could activate ARC POMC neurons and stimulate POMC expression by increasing the mRNA level [28,29,30].
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