Serotonin (5-HT), primarily produced in CNS raphe nuclei and gut, plays a wide-ranging modulatory role at the level of several homeostatic responses. In particular, CNS 5-HT regulates many amongst the main individual adaptive-relational abilities to react to environmental changes, such as feeding behavior, thermoregulation, motor activity, libido, cognition, impulsivity, aggressiveness, nociception and mood. Besides, 5-HT also acts on peripheral tissues and organs, modulating the immune and flogistic responses, as well as blood stem cells differentiation, hemodynamic function and intestinal peristalsis . Despite 5-HT has been extensively studied in recent years, the link between the expression of 5-HT transporter (SERT), the pivotal protein regulating its extra- and intra-cell concentrations, and human obesity has been supported by few studies. By single-photon emission tomography (SPECT) analysis in midbrain areas of obese women affected by binge eating disorder (BED), a reduction in SERT density has been reported , and this reduction was rescued by SSRI therapy .
A more recent in vivo PET study, using a iodinate tracer ([123I]-nor-β-CIT) in midbrain areas of monozygotic twins, has shown a higher SERT density in co-twins with higher BMI . The latter study was conducted in the Finnish population, (presenting a reduced genetic variance than other human ethnic groups) and selected twins were prevalently women.
Conversely, other PET investigations on unrelated healthy volunteers using a different SERT ligand ([11C]-DASB), have shown a negative correlation between cerebral SERT expression and BMI [49, 50]. Our study clearly demonstrates a reduced SERT number in platelet membranes of severely obese subjects (> 35 kg/m2) and a negative correlation between platelet SERT Bmax and BMI in human obesity. Instead, the lack of significant changes in the SERT affinity parameter KD suggests a comparable SERT protein conformation in lean and obese individuals. All these studies substantiate the link between 5-HT activity, SERT expression and weight gain, but discrepancies are present. An explanation of this discrepancy can be found putting all these data in the context of SERT regulatory pathways.
As introduced before, protein SERT expression is a model of “fine-tuned” regulation of membrane-bound proteins. Beside undergoing a short-term up and down-regulation, SERT presence in cell membranes can be long-term modulated through positive and negative signals, allowing long-lasting cell adaptation to the extracellular content of 5-HT or other related stimuli. The balance between the converging short and long-term regulatory pathways of SERT defines its expression and affinity states during developmental stages, under physiological and pathological conditions.
We have previously shown that SERT protein expression in platelets (in plasma membrane and intracellular pools) is regulated by megakaryoblast cell differentiation processes . We have also reported an up-regulated translocator protein TSPO expression in discrete brain regions of ob/ob mice, without appreciable changes in SERT number either in the brain or in platelets . Since leptin has been found to down-regulate SERT expression , we hypothesized that ob/ob animals, during their development, can modulate SERT expression through the activation of alternative regulatory pathways, without excluding modified SERT reserve and 5-HT responsiveness. In the present study, a reduced platelet SERT in severe obese subjects (grade II and III) has been shown. This finding mirrors at the peripheral levels what previously reported in the brain . In contrast to mutant leptin-lacking ob/ob mice, a link between human obesity, often associated with high serum leptin [54, 55] and SERT regulatory cascades leading to its reduction or internalization can be hypothesized. The implications of regulatory mechanisms on reduced SERT expression in obesity is indirectly supported by studies conducted on double knockout SERT(−/−)/brain derived neurotrophic factor (BDNF) (+/−) mice [56, 57] revealing the regulatory role of either other monoamine protein markers or trophic factors on 5-HT physiology and activity on body weight balance. Nevertheless, currently, a clear explanation for the lower SERT expression found in platelets of severe obese individuals is lacking. Platelet 5-HT can be part of a network involving adipokines, cytokines and inflammatory responses . This is supported by the report of adipocytes expressing 5-HT receptor subtypes  and, more recently, even SERT , suggesting that adipose tissue and 5-HT system interact with each other. It is possible that the reduced SERT expression is due to impaired 5-HT synthesis and activity in obese subjects [3, 61], as reported for neurotic behaviors and personality traits, and that altered SERT/5-HT receptors and/or SERT regulation underscore obesity. In this study, none of the recruited subjects had a present or past history of a major psychiatric disorder, but some of them could present personality traits that could be possibly linked to susceptibility to obesity [57, 62]. On the other side, imbalanced appetite hormones, adipokines or gut hormones could counter-regulate SERT expression.
The controversy between reduced SERT expression in obese subjects and increased midbrain SERT in acquired obesity, as reported in monozygotic co-twins with a higher BMI , can be explained by different SERT regulatory processes during gene-environment interactions. Specifically, the selection criteria applied in the Finnish study could have included higher BMI co-twins under particular lifestyles and/or changes of dietary habits leading to SERT up-regulation, as observed in rodent models of acquired obesity . At the same time, considering the experimental design of the Finnish study, selected twins could also bear a genotype linked to vulnerability to stress as SERT-reducing obese subjects . Moreover, of note, our investigation and that by Erritzoe et al. (2011)  much differ from the Finnish study  in terms of: a) evaluated BMI ranges; b) employed technical procedures (e.g., PET vs. in vitro binding experiments carried in membranes; different SERT binding tracers); c) sample size of recruited subjects.
Despite the well-known gender-related differences in obesity and fat distribution, we did not found appreciable differences in Bmax/BMI ratios in males vs. females, suggesting a gender-independent effect of BMI on SERT expression in platelets of severe obese individuals.