Abstract
Central and peripheral serotonin (5-hydroxytryptamine, 5-HT) regulate feeding signals for energy metabolism. Disruption of central 5-HT signaling via 5-HT2C receptors (5-HT2CRs) induces leptin-independent hyperphagia in mice, leading to late-onset obesity, insulin resistance, and impaired glucose tolerance. 5-HT2CR mutant mice are more responsive than wild-type mice to a high-fat diet, exhibiting earlier-onset obesity and type 2 diabetes. High-fat and high-carbohydrate diets increase plasma 5-HT and fibroblast growth factor-21 (FGF21) levels. Plasma 5-HT and FGF21 levels are increased in rodents and humans with obesity, type 2 diabetes, and non-alcohol fatty liver diseases (NAFLD). The increases in plasma FGF21 and hepatic FGF21 expression precede hyperinsulinemia, insulin resistance, hyperglycemia, and weight gain in mice fed a high-fat diet. Nutritional, pharmacologic, or genetic inhibition of peripheral 5-HT synthesis via tryptophan hydroxylase 1 (Tph1) decreases hepatic FGF21 expression and plasma FGF21 levels in mice. Thus, perturbing central 5-HT signaling via 5-HT2CRs alters feeding behavior. Increased energy intake via a high-fat diet and/or high-carbohydrate diet can upregulate gut-derived 5-HT synthesis via Tph1. Peripheral 5-HT upregulates hepatic FGF21 expression and plasma FGF21 levels, leading to metabolic diseases such as obesity, insulin resistance, type 2 diabetes, and NAFLD. The 5-HT network in the brain–gut–liver axis regulates feeding signals and may be involved in the development and/or prevention of metabolic diseases.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine derived from tryptophan
Peripheral 5-HT is synthesized by tryptophan hydroxylase 1 (Tph1), which is mainly expressed in the enterochromaffin (EC) cells of the gut, whereas central 5-HT is synthesized by Tph2, which is predominantly expressed in the raphe nuclei of the brainstem [1]
Among the 5-HTR subtypes expressed in the hypothalamic regions that are implicated in regulating appetite and energy metabolism, including 5HT1AR, 5-HT1BR, 5-HT2AR, 5-HT6R and 5-HT7R, gene knockout studies have focused on 5-HT2CRs
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine derived from tryptophan. Peripheral 5-HT is synthesized by tryptophan hydroxylase 1 (Tph1), which is mainly expressed in the enterochromaffin (EC) cells of the gut, whereas central 5-HT is synthesized by Tph, which is predominantly expressed in the raphe nuclei of the brainstem [1]. GPCR, G-protein coupled receptor; cAMP, cyclic adenosine monophosphate; AC, adenylate cyclase; IP3, inositol triphosphate; DAG, diacylglycerol; PKC, proteinkinase C; PKA, proein kinase A Pharmacologic compounds such as fenfluramine and sibutramine, which increase 5-HT release and/or inhibit 5-HT reuptake, and exhibit anti-obesity effects that appear to be mediated by 5-HT2CRs [4,5]; these drugs were withdrawn from the international market, due to their cardiac side effects via the activation of 5-HT2BRs. Pharmacologic compounds such as fenfluramine and sibutramine, which increase 5-HT release and/or inhibit 5-HT reuptake, and exhibit anti-obesity effects that appear to be mediated by 5-HT2CRs [4,5]; these drugs were withdrawn from the international market, due to their cardiac side effects via the activation of 5-HT2BRs Another drug, lorcaserin, which is a selective 5-HT2CR agonist, induces clinically meaningful weight loss and was approved by the Food and Drug Administration (FDA) as a new anti-obesity agent in 2012 [6]. Chronic hyperphagia and decreased sympathetic neural activity in white adipose tissue in relation to the decreased activity-related energy cost may contribute to the middle age-onset of obesity in 5-HT2CR mutants
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