Abstract
BackgroundSerotonin (5-HT) is a well-known modulator of eating behavior. However, the molecular mechanisms linking its action to body weight balance have been only partially elucidated. Since platelets are a suitable peripheral model to study 5-HT transport, metabolism and release, we herein evaluated the expression of the platelet 5-HT re-uptake system (SERT) by [3H]-paroxetine binding assay. A cohort of 114 unrelated individuals (34 males, 80 females; age, mean ± SD: 38.57 ± 12.47 years) without major psychiatric disorders, was recruited following a naturalistic design regarding age or gender and classified accordingly to their body mass index (BMI). Subjects were divided into 5 groups: normal-weight (NW), overweight (OW) and grade I-III obese (OB) individuals. For gender analyses, data were transformed into [3H]-paroxetine density (Bmax)/BMI ratios to overcome both the disparity of women vs. men number and anthropometric differences between sexes.Results[3H]-paroxetine Bmax (SERT density, fmol/mg proteins) was reduced in platelet membranes of grade II (p < 0.01) and III (p < 0.001) obese subjects vs. controls and in overweight subjects (p < 0.05) vs. grade III obese individuals. Considering all patients together, a strong negative correlation between Bmax and BMI (r = −0.449; P < 0.0001) was demonstrated. Conversely, [3H]-paroxetine KD (dissociation constant, nM) did not differ among groups. No gender-related variation concerning Bmax/BMI ratios was observed in this cohort of subjects.ConclusionsThe down-regulation of SERT in platelet membranes of severe human obesity (BMI > 35 Kg/m2) confirms the involvement of 5-HT system in body weight gain. Moreover, this findings may help to elucidate those monoamine-endocrine networks acting on fat storage, adipocyte signaling and energy balance. Targeting 5-HT/5-HT-related markers will possibly uncover the existence of human obesity subtypes.
Highlights
Serotonin (5-HT) is a well-known modulator of eating behavior
[3H]-paroxetine binding experiments Equilibrium saturation and Scatchard analysis of [3H]paroxetine specific binding showed a single population of high-affinity recognition sites in platelet membranes from all the subjects under investigation, clearly indicating the labeling of a single protein
ANOVA analysis showed a significant difference between the [3H]paroxetine Bmax means of the 5 body mass index (BMI) groups (p < 0.0001); after the post-hoc Bonferroni correction test, Bmax mean values were significantly reduced in OB subjects class II-III (BMI > 35 kg/m2) vs. normal weight subjects (NWs) (p < 0.01 and p < 0.001, respectively) (Figure 1a); Bmax values were decreased in OB-IIIs respect to OWs (p < 0.05) (Figure 1a)
Summary
Serotonin (5-HT) is a well-known modulator of eating behavior. the molecular mechanisms linking its action to body weight balance have been only partially elucidated. SERT is a glycoprotein belonging to the super-family of membranebound NaCl-dependent neurotransmitter transporters, characterized by 12 putative membrane spanning domains: it promotes 5-HT clearance (re-uptake) from the extracellular milieu and modifies the sensitization state of 5-HT receptors within the nervous system or non-neural districts (gut, platelets, lymphomonocytes) [31,32]. It is a pharmacologically active site, the target of re-uptake inhibitors as tricyclic antidepressants (TCA) and Selective Serotonin Reuptake Inhibitors (SSRIs) or 5-HT releasers like fenfluramine and 3,4-methylenedioxy-N-methamphetamine (MDMA) [33]. Both SERT expression and 5HT uptake function are finely tuned by protein-kinases activities and gene transcription which control, following cell necessities, conformational changes of the membranebound SERT protein and/or the degree of SERT partition between cytoskeleton and plasma membrane [34,35,36,37]
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