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Endogenous serotonergic tone as a modulator of metabolic homeostasis and response to metabolic challenge

A remarkable extent to which central and peripheral serotonin (5HT) signaling impacts the regulation of energy balance and, consequently, the obesity and other metabolic disorders, has been recognized recently. Many of the molecular mechanisms underlying serotonin action in the body weight regulation have been identified, but for comprehensive understanding of serotonin- mediated control of energy homeostasis, studies from a whole-body perspective are essential. In search for the interplay between endogenous serotonin tone and metabolic homeostasis, we use a genetic model of rats (Wistar-Zagreb 5HT rats) with constitutionally altered whole body serotonin system (hyper/hyposerotonergic). The two sublines (high-/low-5HT subline) of the model were developed by selective breeding of rats toward extremes of peripheral (platelet) 5HT transporter activity. Animals from the high-5HT subline show an increased body weight and elevated visceral adiposity as compared to the low-5HT animals, prompting us to investigate metabolic differences between sublines in both, physiological conditions and in response to specific metabolic challenge (high-fat diet). We have compared 5HT sublines for biochemical parameters (glucose, lipid profile, adipocytokines levels) in blood plasma, expression of genes for relevant metabolic players (cytokines, transcription factors) in white adipose tissue as well as their functional responses to glucose and insulin loading. Result show that, in addition to increased body weight and adiposity, high 5HT tone of animals was associated with increased blood glucose and lipids, while adipocytokine (leptin) levels differed only in the fed state of animals. Functionally, high-5HT rats were glucose intolerant and insulin resistant in comparison to the low-5HT subline. On the other hand, the low 5HT animals showed more pronounced functional consequences of high-fat diet, specifically, the body weight accumulation, increase in plasma glucose level and the response in glucose tolerance and insulin tolerance tests. In conclusion, results show a complex interrelation between endogenous 5HT activity and metabolic (dys)regulation. In addition, our Wistar-Zagreb 5HT rats could probably be a usefull animal model to study the (integrative) serotonergic mechanisms in dysmetabolic states such as obesity and insulin resistance.

obesity ; glucose ; insulin resistance ; high-fat diet ; serotonin ; Wistar-Zagreb 5HT rats

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