Constitutive Serotonin Tone as a Modulator of Brown Adipose Tissue Thermogenesis: A Rat Study.

Brown adipose tissue (BAT), an important regulator of thermogenic and metabolic processes, is considered a promising target to combat metabolic disorders. The neurotransmitter and hormone serotonin (5HT) is a major modulator of energy homeostasis, with its central and peripheral pools acting in opposing ways. To better understand how individual variations in 5HT homeostasis influence the thermogenic functionality of BAT, we used a rat model consisting of two sublines with constitutively increased (high-5HT) or decreased (low-5HT) whole-body 5HT tone, developed by selective breeding for platelet 5HT parameters. We have shown that animals with constitutively low 5HT activity maintained at a standard housing temperature (22 °C) have greater interscapular BAT (iBAT) mass and higher iBAT metabolic activity (as evidenced by measurements of iBAT temperature and glucose uptake), accompanied by increased iBAT mRNA expression of key thermogenic genes, compared to animals with high 5HT tone. In response to further thermogenic challenges-intermittent cold exposure or treatment with a ß3-adrenergic agonist-5HT sublines show several functional and molecular differences linking constitutively low endogenous 5HT tone to higher BAT activity/capacity. Overall, the results support a role of 5-HT in the control of BAT thermogenesis They also suggest that individuals with lower 5HT activity may be more sensitive to ß3-adrenergic drugs.

Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone.

Maintaining energy balance is a complex physiological function whose dysregulation can lead to obesity and associated metabolic disorders. The bioamine serotonin (5HT) is an important regulator of energy homeostasis, with its central and peripheral pools influencing energy status in opposing ways. Using sublines of rats with constitutionally increased (high-5HT) or decreased (low-5HT) whole-body 5HT tone, we have previously shown that under standard diet constitutionally higher 5HT activity is associated with increased body weight, adiposity, and impaired glucose homeostasis. Here, we investigated the response of 5HT sublines to an obesogenic diet. Consistent with previous findings, high-5HT animals fed a standard diet had poorer metabolic health. However, in response to a high-fat diet, only low-5HT animals increased body weight and insulin resistance. They also showed more pronounced changes in blood metabolic parameters and the expression of various metabolic genes in hypothalamus and adipose tissue. On the other hand, high-5HT animals appeared to be protected from major metabolic disturbances of the obesogenic diet. The results suggest that constitutionally low 5HT activity is associated with higher susceptibility to harmful effects of a high-energy diet. High-5HT subline, which developed less adverse metabolic outcomes on hypercaloric diets, may prove useful in understanding metabolically healthy obesity in humans.

Differential Serotonin Uptake Mechanisms at the Human Maternal-Fetal Interface.

Serotonin (5-HT) plays an extensive role during pregnancy in regulating both the placental physiology and embryonic/fetal development. The uptake of 5-HT into cells is central to the control of local concentrations of 5-HT near its molecular targets. Here, we investigated the mechanisms of 5-HT uptake into human primary placental cells and cord blood platelets, all isolated immediately after birth. Trophoblasts and cord blood platelets showed 5-HT uptake with similar Michaelis constant (Km) values (~0.6 µM), typical of the high-affinity serotonin transporter (SERT). The uptake of 5-HT into trophoblasts was efficiently inhibited by various SERT-targeting drugs. In contrast, the uptake of 5-HT into feto-placental endothelial cells was not inhibited by a SERT blocker and showed a Km value (~782 µM) in the low-affinity range. Consistent with this, SERT mRNAs were abundant in term trophoblasts but sparse in feto-placental endothelial cells, whereas the opposite was found for the low-affinity plasma membrane monoamine transporter (PMAT) mRNAs. Organic cation transporter (OCT) 1, 2, and 3 mRNAs were absent or sparse in both cell types. In summary, the results demonstrate, for the first time, the presence of functional 5-HT uptake systems in feto-placental endothelial cells and fetal platelets, cells that are in direct contact with fetal blood plasma. The data also highlight the sensitivity to various psychotropic drugs of 5-HT transport into trophoblasts facing the maternal blood. The multiple, high-, and low-affinity systems present for the cellular uptake of 5-HT underscore the importance of 5-HT homeostasis at the maternal-fetal interface.

Metabolic Disturbances in Rat Sublines with Constitutionally Altered Serotonin Homeostasis.

Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally high or low 5HT activity and systemic net energy balance. Two sublines of rats with high and low whole-body 5HT tone, obtained by selective breeding for platelet 5HT parameters, were examined for fat accumulation in different white adipose tissue (WAT) depots, glucose/insulin tolerance, blood metabolic parameters, and expression of various metabolic genes. High-5HT animals, unlike their low-5HT counterparts, developed widespread intra-abdominal obesity associated with glucose and insulin intolerance, which worsened with age. They also had elevated blood glucose and lipid parameters but showed no significant changes in circulating leptin, resistin, and adipsin levels. Surprisingly, adiponectin levels were increased in plasma but reduced in the WAT of high-5HT rats. A limited number of metabolic genes belonging to different functional classes showed differential expression in WAT of high-5HT compared to low-5HT rats. Overall, a constitutive increase in 5HT tone is associated with a positive energy balance acting through subtle dysregulation of a broad spectrum of metabolic pathways.

Constitutionally High Serotonin Tone Favors Obesity: Study on Rat Sublines With Altered Serotonin Homeostasis.

Central and peripheral pools of biogenic monoamine serotonin (5-hydroxytryptamine [5HT]) exert opposite effects on the body weight regulation: increase in brain 5HT activity is expected to decrease body weight, whereas increase in peripheral 5HT activity will increase body weight and adiposity. In a genetic model of rats with constitutionally high- or low-5HT homeostasis (hyperserotonergic/hyposerotonergic rats), we have studied how individual differences in endogenous 5HT tone modulate net energy balance of the organism. The high-5HT and low-5HT sublines of the model were developed by selective breeding toward extreme platelet activities of 5HT transporter, a key molecule determining 5HT bioavailability/activity. In animals from high-5HT and low-5HT sublines, we assessed physiological characteristics associated with body weight homeostasis and expression profile of a large scale of body weight-regulating genes in hypothalamus, a major brain region controlling energy balance. Results showed that under standard chow diet animals from the high-5HT subline, as compared to low-5HT animals, have lifelong increased body weight (by 12%), higher absolute daily food intake (by 9%), and different pattern of fat distribution (larger amount of white adipose tissue and lower amount of brown adipose tissue). A large number of body weight-regulating hypothalamic genes were analyzed for their mRNA expression: 24 genes by reverse transcription-quantitative polymerase chain reaction (n = 9-10 rats/subline) including neuropeptides and their receptors, growth factors, transcriptional factors, and receptors for peripheral signals, and a total of 84 genes of various classes by polymerase chain reaction array (pools of six rats/subline). Only few genes showed significant differences in mRNA expression levels between 5HT sublines (e.g. neuropeptide Y receptor, fibroblast growth factor 10), but high-5HT animals displayed a clear trend to upregulation of mRNAs for a number of orexigenic signaling peptides, their receptors, and other molecules with orexigenic activity. Receptors for peripheral signals (leptin, insulin) and molecules in their downstream signaling were not altered, indicating no changes in central insulin/leptin resistance. At the protein level, there were no differences in the content of hypothalamic leptin receptor between 5HT sublines, but significant sex and age effects were observed. Results show that higher constitutive/individual 5HT tone favors higher body weight and adiposity probably due to concurrent upregulation of several hypothalamic orexigenic pathways.