Franziska Zientek

No association between striatal dopamine transporter binding and body mass index: A multi-center European study in healthy volunteers

INTRODUCTION Dopamine is one among several neurotransmitters that regulate food intake and overeating. Thus, it has been linked to the pathophysiology of obesity and high body mass index (BMI). Striatal dopamine D(2) receptor availability is lower in obesity and there are indications that striatal dopamine transporter (DAT) availability is also decreased. In this study, we tested whether BMI and striatal DAT availability are associated. METHODS The study included 123 healthy individuals from a large European multi-center database. They had a BMI range of 18.2-41.1 kg/m(2) and were scanned using [(123)I]FP-CIT SPECT imaging. Scans were analyzed with both region-of-interest and voxel-based analysis to determine the binding potential for DAT availability in the caudate nucleus and putamen. A direct relation between BMI and DAT availability was assessed and groups with high and low BMI were compared for DAT availability. RESULTS No association between BMI and striatal DAT availability was found. CONCLUSION The lack of an association between BMI and striatal DAT availability suggests that the regulation of striatal synaptic dopamine levels by DAT plays no or a limited role in the pathophysiology of overweight and obesity.

Association of central serotonin transporter availability and body mass index in healthy Europeans.

UNLABELLED Serotonin-mediated mechanisms, in particular via the serotonin transporter (SERT), are thought to have an effect on food intake and play an important role in the pathophysiology of obesity. However, imaging studies that examined the correlation between body mass index (BMI) and SERT are sparse and provided contradictory results. The aim of this study was to further test the association between SERT and BMI in a large cohort of healthy subjects. METHODS 127 subjects of the ENC DAT database (58 females, age 52 ± 18 years, range 20-83, BMI 25.2 ± 3.8 kg/m(2), range 18.2-41.1) were analysed using region-of-interest (ROI) and voxel-based approaches to calculate [(123)I]FP-CIT specific-to-nonspecific binding ratios (SBR) in the hypothalamus/thalamus and midbrain/brainstem as SERT-specific target regions. RESULTS In the voxel-based analysis, SERT availability and BMI were positively associated in the thalamus, but not in the midbrain. In the ROI-analysis, the interaction between gender and BMI showed a trend with higher correlation coefficient for men in the midbrain albeit not significant (0.033SBRm(2)/kg, p=0.1). CONCLUSIONS The data are in agreement with previous PET findings of an altered central serotonergic tone depending on BMI, as a probable pathophysiologic mechanism in obesity, and should encourage further clinical studies in obesity targeting the serotonergic system.

Serotonin transporter gene promoter methylation status correlates with in vivo prefrontal 5-HTT availability and reward function in human obesity

A polymorphism in the promoter region of the human serotonin transporter (5-HTT)-coding SLC6A4 gene (5-HTTLPR) has been implicated in moderating susceptibility to stress-related psychopathology and to possess regulatory functions on human in vivo 5-HTT availability. However, data on a direct relation between 5-HTTLPR and in vivo 5-HTT availability have been inconsistent. Additional factors such as epigenetic modifications of 5-HTTLPR might contribute to this association. This is of particular interest in the context of obesity, as an association with 5-HTTLPR hypermethylation has previously been reported. Here, we tested the hypothesis that methylation rates of 14 cytosine–phosphate–guanine (CpG) 5-HTTLPR loci, in vivo central 5-HTT availability as measured with [11C]DASB positron emission tomography (PET) and body mass index (BMI) are related in a group of 30 obese (age: 36±10 years, BMI>35 kg/m2) and 14 normal-weight controls (age 36±7 years, BMI<25 kg/m2). No significant association between 5-HTTLPR methylation and BMI overall was found. However, site-specific elevations in 5-HTTLPR methylation rates were significantly associated with lower 5-HTT availability in regions of the prefrontal cortex (PFC) specifically within the obese group when analyzed in isolation. This association was independent of functional 5-HTTLPR allelic variation. In addition, negative correlative data showed that CpG10-associated 5-HTT availability determines levels of reward sensitivity in obesity. Together, our findings suggest that epigenetic mechanisms rather than 5-HTTLPR alone influence in vivo 5-HTT availability, predominantly in regions having a critical role in reward processing, and this might have an impact on the progression of the obese phenotype.

The association between in vivo central noradrenaline transporter availability and trait impulsivity

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[11C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8±9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m2 to 47.8kg/m2. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.

Effortful control as a dimension of temperament is negatively associated with prefrontal serotonin transporter availability in obese and non‐obese individuals

There is evidence that temperamental factors are associated with obesity; however, the biological mechanism of such association remains elusive. We aimed to investigate a possible association between serotonin transmission and regulative temperament in obese and non‐obese individuals by using positron emission tomography (PET) imaging of serotonin transporters (SERT) and the Adult Temperament Questionnaire. Twenty‐nine obese individuals with body mass index (BMI) ≥ 35 kg/m2 and 13 non‐obese controls (BMI < 30 kg/m2) underwent PET with [11C]‐labeled DASB (highly selective for SERT) and self‐completed the Effortful Control (EC) scale of the Adult Temperament Questionnaire‐Short Form (ATQ). With the help of this questionnaire, we aimed to assess the capacity of self‐regulation. Overall, for obese and non‐obese individuals together, VOI‐based (volume of interest) analysis showed significant negative correlations between SERT BPND and ATQ‐EC AC (Activation Control) subscale in several brain regions (all r ≤ −0.47). Obese and non‐obese individuals separated showed equally strong positive, but non‐significant correlations. The analysis did not reveal any significant correlations of SERT availability and ATQ‐EC IC (Inhibitory Control) or ATQ‐EC AtC (Attentional Control) subscale within and between the two groups. The results indicate that regulative temperament – particularly the capacity to mitigate negatively toned impulses and to resist inappropriate avoidance behavior – might be associated with the prefrontal serotonergic system.