The Effect of Obesity on the Availabilities of Dopamine and Serotonin Transporters

The authors investigated relations between obesity, age, and sex and the availabilities of striatal dopamine transporter (DAT) and extrastriatal serotonin transporter (SERT) by 123I-FP-CIT single-photon emission computed tomography. The study population consisted of 192 healthy controls with screening 123I-FP-CIT scans. Specific bindings of 123I-FP-CIT to DAT and SERT were calculated using regions of interest. Specific binding ratios (SBRs) of DAT and SERT except pons (r = 0.2217, p = 0.0026), were not correlated with body mass index (BMI). SBRs of midbrains correlated negatively with the BMIs of obese subjects (r = −0.3126, p = 0.0496), and positively with the those of non-obese subjects (r = 0.2327, p = 0.0053). SBRs of caudate nucleus (r = −0.3175, p < 0.0001), striatum (r = −0.226, p = 0.0022), and thalamus (r = −0.1978, p = 0.0074) reduced with age, and SERT availability was higher in males. However, DAT availability was similar in males and females. In conclusion, obesity has an effect on midbrain SERT availability. In addition, BMI was correlated with pontine SERT availability but not with striatal DAT availability. SERT availability was higher in males, but DAT availability showed no gender predilection.

interfere with DAT SPECT scans, anticoagulants that might preclude safe completion of lumbar puncture, investigational drugs, and a condition that precluded the safe performance of routine lumbar puncture. Medical histories, results of neurological examinations (motor and non-motor assessments), and 123 I-FP-CIT SPECT scans were downloaded. 123 I-FP-CIT SPECT. 123 I-FP-CIT SPECT was performed during screening visits. SPECT scans were acquired 4 ± 0.5 hrs after injecting 111-185 MBq of 123 I-FP-CIT. Subjects were pretreated with iodine solution or perchlorate prior to injection to block thyroid uptake. Raw data were acquired into a 128 × 128 matrix stepping each 3 or 4 degrees for total projections. Raw projection data were reconstructed using the iterative ordered subset expectation maximization and HERMES (Hermes Medical Solutions, Stockholm, Sweden). Reconstructed images were transferred to pmod (PMOD Technologies LLC, Zürich, Switzerland) for subsequent processing, including attenuation correction. Image analysis. Downloaded scans were loaded using pmod v3.6 (PMOD Technologies LLC, Zürich, Switzerland) using a single subject MRI template in Montreal Neurological Institute space 19 . Specific bindings of 123 I-FP-CIT to DAT and SERT were calculated by region of interest (ROI) analysis. A standard set of volumes of interest (VOIs) defining putamen, caudate nucleus, striatum (putamen + caudate nucleus), and thalamus as described by the Automated Anatomical Labeling (AAL) atlas 20 , and spherical VOIs for pons and midbrain were defined. The cerebellum was chosen as a reference region. A VOI template was applied to measure specific binding ratios (SBRs) of caudate nucleus, putamen, striatum, thalamus, pons, and midbrain as follows; SBR = (target-cerebellum)/cerebellum. Statistical analysis. Pearson correlation was used to measure the linear dependences between SBRs and body mass indices (BMIs). For comparisons between obese and non-obese subjects, analyses of covariance was performed using SBR as a dependent variable, BMI as an independent variable, and age as a covariate. The T-test was used to compare the SBRs of males and females. The analysis was performed using GraphPad Prism 7 for Mac OS X (GraphPimad Software Inc, San Diego, CA, USA). Data availability. Data used in the preparation of this article were obtained from PPMI database (www. ppmi-info.org/data).

Discussion
To the best of our knowledge, this is the largest study undertaken to investigate the effect of obesity on the availabilities of DAT and SERT in healthy controls. In this study, obesity has an effect on midbrain SERT availability. Striatal DAT availability was not correlated with BMI, but pontine SERT availability was found to be positively correlated with BMI. SERT availability was higher in men, but DAT availability was not.
Obesity arises from energy imbalance, whereby energy intake exceeds energy expenditure 21 . This imbalance can be triggered by the internal state of the caloric equation (homeostasis) and by non-homeostatic factors, such as, social, cultural, psychological, environmental factors, food type and the amount consumed [22][23][24] . In industrialized countries where foods are plentiful, food palatability in increases food intake via a reward mechanism 25 . Dopamine is a neurotransmitter that modulates reward 9 . Repeated exposure to a food reward, reduces the activation of dopamine and induces habituation 26 , as this blunted activation can trigger compensatory overeating 27 . Therefore, decreased sensitivity to the rewarding effects of food consumption due to reduced dopaminergic neuron activation develops in obesity 28 . In this regard, previous studies have focused on the role of DAT and SERT in obesity. Of three studies that investigated the correlation between BMI and DAT 29-31 , one study, in which 99m Tc-TRODAT was used, reported a significant correlation coefficient of −0.44 29 . However, in most studies no association was found between BMI and DAT availability 30,31 , which is consistent with our observations. DAT Obese (n = 40) Non-obese (n = 142) p value   controls extracellular dopamine levels by selectively uptaking dopamine into presynaptic neurons 32 . However, we observed no significant correlation between DAT and BMI. It has been suggested postsynaptically located dopamine receptor might play a dominant role in the reward system 33 . Although previous researches have mainly focused on the role played by dopamine in the reward system, serotonin is also known to play an important role in reward processing 34 . In a previous study, a negative correlation was observed between SERT and BMI was reported using global neocortex, midbrain, and striatum as target regions and the SERT selective radiotracer, 11 C-DASB 35 . However, a voxel-based analysis of 123 I-FP-CIT found a positive correlation between BMI and SERT availability in thalamus 36 , and Versteeg RI et al. 31 and Hesses S et al. 37 found no significant association between SERT availability and BMI. In the present study, SERT availability in pons was positively correlated with BMI. Higher SERT recruitment may be a consequence of higher serotonin recruitment due to food overload or overactive reward and homeostatic circuits 38 . Interestingly, SERT availabilities in midbrain were negatively and positively correlated with BMIs in obese and non-obese subjects, respectively. BMI might reflect a different role in predicting serotonergic tonus in midbrain. Thus, we hypothesized that SERT availability increases with BMI in response to serotonin in non-obese subjects. Hinderberger P et al. 39 found SERT availability in the nucleus accumbens was negatively correlated in non-obese subjects and positively correlated in obese subjects with serum brain-derived neurotrophic factor levels, which are negatively correlated with BMI 40 . Therefore, SERT availability in the nucleus accumbens might present similar slopes to those observed in the present study. Serotonin receptor availability is negative correlated with serotonin levels 41 , and SERT availabilities in severely obese subjects were reported to be no different from those of lean subjects 37 , but those of overweight/moderately obese subjects were higher than those of lean subjects 42 . van Galen et al. suggested an inversed parabolic relationship between SERT availability and serotonin levels 43 , which is consistent with our findings. However, no previous study has reported a significant link between BMI and SERT availability 42,43 , and thus, this is the first study to describe the effect of obesity on midbrain SERT availability. Because there is no direct means of measuring dopamine or serotonin concentrations in human brain, we chose to examine DAT and SERT availabilities as determined by 123 I-FP-CIT SPECT 44 . DAT and SERT availabilities are influenced by radioligand affinity and are sensitive to changes in neurotransmitter concentration, and thus, these factors must be taken into account when interpreting neuroimages 44 . Furthermore, some controversy exists regarding the interpretations of results obtained using radiopharmaceuticals 44 . For example, an increase in SERT can be interpreted as an increase in serotonin level in synapses, or as increased serotonin clearance from extracellular regions in the brain, and thus, interpretations of the opposite effect of obesity on midbrain SERT availability may be less than straightforward.
Age related decreases in DAT 45 and SERT 45,46 have been well documented, and were also observed in the present study. However, DAT and SERT availability differences are controversial. Previous studies have reported higher SBRs in striatum 47 and thalamus 15 in females, but higher SBRs in pons in males 15 . In the present study, SERT availability was higher in males, but DAT availability was similar in men and women. Therefore, although sex hormones affect serotonin 48 and dopamine 49 , serotonin neurotransmission may be more susceptible to gender.
This study has several limitations that warrant consideration. First, although this is the largest 123 I-FP-CIT SPECT study conducted on the topic, data acquisition procedures at multiple sites may have been differed. Second, for normal subjects included in PPMI, 123 I-FP-CIT SPECT was performed once at baseline enrollment, and thus, further longitudinal studies are needed to investigate the association between the availabilities of DAT and SERT and subject weight changes. Third, we investigated the associations between neuroimaging findings and BMI, and thus, additional studies are needed to investigate the effects of food intake, food stimulation, and glucose loading in obese and lean subjects. Forth we used BMI to define obesity and although BMI is the most commonly used parameter, it might not be (is not?) directly related to body fat levels 50 .
In conclusion, obesity has an effect on midbrain SERT availability. In addition, BMIs were not found to be correlated with striatal DAT availability, but rather with pontine SERT availability. Furthermore, SERT availability was greater in men, whereas DAT availability was similar in men and women.