The Regulatory Role of the Central and Peripheral Serotonin Network on Feeding Signals in Metabolic Diseases

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.

Keywords: 5-HT2CRs; FGF21; NAFLD; Tph1; energy metabolism; feeding signals; obesity; serotonin; type 2 diabetes.

Figure 1

The regulatory role of the central and peripheral 5-HT network on feeding signals in metabolic diseases. The NTS and hypothalamus can regulate feeding behavior. Feeding behavior can alter the gut-derived 5-HT synthesis via Tph1 and circulating 5-HT levels. Circulating 5-HT and other factors can modulate hepatic FGF21 expression and circulating FGF21 levels. Feeding condition can alter hypothalamic neurotransmission including 5-HT2CR and 5-HT1BR signaling. Microbial metabolites and the gut-derived peptides can modulate central neurotransmission via the afferent vagus nerve to the NTS. Disruption of central 5-HT2CR signaling can decrease hypothalamic POMC and NUCB2 activity and increase hypothalamic orexin activity, leading to overeating. Increased energy intake via a high-fat diet and/or high-carbohydrate diet can upregulate the gut-derived 5-HT synthesis and circulating 5-HT levels. Circulating 5-HT can upregulate hepatic FGF21 expression and circulating FGF21 levels, which can precede hyperinsulinemia, insulin resistance, type 2 diabetes and NAFLD. Moreover, hepatic 5-HT2AR and 5-HT2BR signaling may be involved in hepatic FGF21 production and the pathophysiological mechanisms of NAFLD and type 2 diabetes.