Effects of bariatric surgery and dietary interventions for obesity on brain neurotransmitter systems and metabolism: A systematic review of positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) studies

Summary This systematic review collates studies of dietary or bariatric surgery interventions for obesity using positron emission tomography and single‐photon emission computed tomography. Of 604 publications identified, 22 met inclusion criteria. Twelve studies assessed bariatric surgery (seven gastric bypass, five gastric bypass/sleeve gastrectomy), and ten dietary interventions (six low‐calorie diet, three very low‐calorie diet, one prolonged fasting). Thirteen studies examined neurotransmitter systems (six used tracers for dopamine DRD2/3 receptors: two each for 11C‐raclopride, 18F‐fallypride, 123I‐IBZM; one for dopamine transporter, 123I‐FP‐CIT; one used tracer for serotonin 5‐HT2A receptor, 18F‐altanserin; two used tracers for serotonin transporter, 11C‐DASB or 123I‐FP‐CIT; two used tracer for μ‐opioid receptor, 11C‐carfentanil; one used tracer for noradrenaline transporter, 11C‐MRB); seven studies assessed glucose uptake using 18F‐fluorodeoxyglucose; four studies assessed regional cerebral blood flow using 15O‐H2O (one study also used arterial spin labeling); and two studies measured fatty acid uptake using 18F‐FTHA and one using 11C‐palmitate. The review summarizes findings and correlations with clinical outcomes, eating behavior, and mechanistic mediators. The small number of studies using each tracer and intervention, lack of dietary intervention control groups in any surgical studies, heterogeneity in time since intervention and degree of weight loss, and small sample sizes hindered the drawing of robust conclusions across studies.

in 2016, 39% of adults had overweight, and 13% had obesity globally. 1The last report from the National Health Service in 2020 estimated that obesity might affect one in every four adults in the United Kingdom (25% of the population). 2esity surgery is the most effective long-term treatment for obesity. 3,4As the number of obesity surgery operations has increased in the last decade, elucidating the mechanisms of action is crucial and a key research goal that may help optimize surgical outcomes by improving patient selection. 5Moreover, understanding the mechanism of action by which each procedure reduces energy intake may eventually facilitate novel non-surgical approaches, including medications. 3,5Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are currently the most commonly performed obesity surgeries worldwide. 4,6Both procedures result in sustained weight reduction with no significant difference in terms of weight loss (20-25%) between the two groups after 5 years post-surgery. 7,8Although both operations decrease gastric volume, the changes in appetitive gut hormones reduce energy intake by affecting the brain, which produces sustained weight loss. 3Moreover, changes in taste, food preference, food hedonics, and food cue reactivity have been seen in some studies after RYGB and VSG surgery. 5,9However, this depends on the particular outcome measures used.[23][24] Non-surgical interventions usually consist of dietary changes and behavioral therapy, with the primary goal of reducing energy intake, increasing physical activity, and various pharmacotherapies. 4Although non-surgical interventions may achieve weight loss, most of the nonpharmacotherapy methods lead to weight regain over the long-term because of compensatory adaptations in body weight regulation, which promote rapid weight regain efficiently. 25nctional neuroimaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT), fMRI, magnetoencephalography, and electroencephalography, are recently developed tools to investigate the brain centers involved in the control of appetite signals, eating behavior, and the pathophysiology of obesity. 26These techniques offer insight into the brain by providing objective and sensitive information, accelerating scientific progress, and facilitating hypothesis testing. 27In brief, PET is an imaging technique that provides semi-quantitative and quantitative measurements of biochemical processes by measuring the density of various neuroreceptor subtypes.These neuroreceptors include dopamine, opioids, noradrenaline, and serotonin. 28PET also measures the transporter availability of certain neurotransmitters and physiological process including measurement of the brain glucose uptake (BGU), fatty acid uptake, and regional cerebral blood flow (rCBF) which reflect local neuronal activity. 26These measurements rely partly on the use of a pharmacological or physiological compound labeled with a positron-emitting radioisotope, such as 18 F, 11 C, and 15 O.
Like PET, SPECT is another imaging method providing information about biochemical and physiological processes.SPECT radiotracers are elements or pharmacological compounds that include radioactive isotopes such as iodine-123 ( 123 I). 26Only PET and SPECT can provide information on a molecular level because specific molecules can be labeled to allow their detection. 29is systematic review will discuss how these neural systems are dysregulated in human obesity and the effects of dietary and surgical weight loss interventions.This will help understand the mechanisms that lead to overeating and the development of obesity, and the mechanisms behind weight loss, by comparing the differences post-intervention with pre-intervention, or participants with versus without obesity, in brain area related to reward processing, homeostatic control of eating behavior, inhibitory control, executive function, and cognition.Moreover, it evaluates the association of changes in brain tracer uptake with clinical outcomes, behavioral changes, and appetitive gut hormones.
To our knowledge, there is no systematic review that has previously investigated the effect of surgical and other nonpharmacological interventions on the brain, other than one conducted in 2013 that examined the impact of obesity surgery on the brain which included only three PET studies (19 PET/SPECT studies have been conducted after 2013). 30Therefore, this systematic review will identify all the available evidence to evaluate and summarize the finding and help identify any literature gaps.

| Aims and objectives
i. Identify PET or SPECT studies in patients with overweight/ obesity examining effects of bariatric surgery or dietary interventions in longitudinal or cross-sectional design.
ii. Summarize and critically review the findings from the studies identified.
iii.Examine the following issues: a. how heterogeneity in study design, methodology, protocol, and analysis might explain discrepancies between studies.b. associations of brain PET/SPECT findings with clinical outcomes, eating behavior measures, and potential mechanistic mediators, for example, gut hormones.This review includes predictive studies that focus on assessing the effects of an intervention on clinical outcomes, eating behavior measures, and potential mechanistic mediators.Cross-sectional studies that looked only at correlations among PET/SPECT and clinical features, eating behavior measures and mechanistic mediators, in participants before any intervention, and studies that only looked at pharmacological interventions are out of the scope of this review.
A systematic review was completed of studies investigating the impact of bariatric surgery and dietary intervention on brain function using PET/SPECT scans.A comprehensive search of the literature was undertaken to obtain information on both longitudinal and crosssectional human studies.

| Inclusion and exclusion criteria
The studies selected for the review included the following criteria.vii.Studies using brain PET/SPECT scanning, including tracers assessing neurotransmitter systems, rCBF, glucose uptake, or uptake of other metabolites.

| Exclusion criteria
i. Studies performed on children <16 years old.
ii.Studies conducted on animals.
iii.Reviews and meetings abstracts.iv.PET/SPECT studies that just assessed the impact of interventions on peripheral tracer binding (such as the heart, gastrointestinal tract, or adipose tissue).v. PET/SPECT studies that only included a pharmacological intervention.

| Database search
An electronic database search was performed to find the articles to form the evidence base for this review.A comprehensive search was performed across multiple databases and journals using PubMed, Web of Science, PsycINFO, MEDLINE, and EMBASE databases within OVID.Reference lists were also examined from individual papers and relevant review articles.

| Keywords/terms used
The detailed keywords and terms used are provided in Data S1 Methods.

| Data extraction
A complete description of all data extraction is available in Data S1 Methods.

| Methodological quality assessment
The reviewer assessed the methodological quality of the articles by using the National Institutes of Health (NIH) Quality Assessment Tool for the following: (i) observational cohort and cross-sectional studies, (ii) before-after (pre-post) studies with no control group, (iii) controlled intervention studies (https://www.nhlbi.nih.gov/healthtopics/study-quality-assessment-tools),including appraisal criteria specific to the study design.For instance, studies were rated based upon the following criteria: exposure-related considerations (timeline relative to outcome measurement, frequency of measure, and categorization of exposure levels); methodological validity of exposure and outcome measurements; participation and post-baseline follow-up rates; adjustment for confounding variables; outcome assessor blinding; and explicitness of aims, sample, and study setting.The summary score of each study was calculated based on applicable questions for that particular study, expressed as a percentage ranging from 0% to 100%.These were categorized into three categories of quality assessment: poor (0-33.3%),fair (33.4-66.6%),good (66.7-100%), which were equated to high, low, and very low risk of bias. 31

| Search results and selection of studies
Using the keywords, 604 articles were identified and 480 of these were screened after duplicates were removed.From these articles, 458 were excluded with only 22 studies meeting the inclusion criteria (Figure 1).

| Country
The country where the studies were conducted are provided in Table 1 and summarised in Data S1 Results: 3.2.2.Country.

| Study design
Study summaries are presented in Table 1.

| Demographic data
Demographic data for individual studies are given in Table 2.

| Study protocols and analysis
Study protocols and PET/SPECT protocols and analysis are summarized in Tables S1-S3.Quality of data and risk of bias is summarized in Table S4 and described in Data S1 Results: 3.4.6.Quality of data.

| Correlations
Association of PET/SPECT findings with clinical outcomes are summarized in Table S6 and described in Data S1 Results: 3.6.1.Clinical outcomes.
Behavioral measures and their association with PET/SPECT findings are summarized in Tables S7 and S8, and described in Data S1 Results: 3.6.2.Behavioral outcomes and 3.6.3.Mood assessment.
Blood mechanistic measures and the association with PET/SPECT findings are summarized in Tables S9 and S10, and described in Data S1 Results: 3.6.4.Mechanistic outcomes.

| DISCUSSION
This literature review of PET/SPECT studies examining neurotransmitter systems and rCBF and metabolite uptake in surgical and non-         38.0 ± 6.9 12.9 ± 6.5% (6.

| Dopamine system
Dopamine plays a major role in motivation, reward, and prediction of reward. 54Dopamine influences food intake via the mesolimbic circuitry (projections from the ventral tegmental area to regions including the ventral and dorsal striatum) by modulating appetitive motivational processes. 55,56Dopaminergic neurotransmission is mediated by five distinct receptor subtypes, which are classified into two main classes of receptors termed D1-like (D1 and D5) and D2-like (D2, D3, and D4). 54[59] Although one small study (n = 5) found an increase in striatal 11 C-raclopride binding potential (BP) at 4-6 weeks after RYGB surgery following $13% weight loss in the majority of women, no formal statistics was performed, 32 while no changes were seen in the striatum (or elsewhere in brain) in a larger study (n = 16) of older women at 6 months after RYGB/VSG surgery despite 23% weight loss. 33Similarly, no change was observed in striatal 123 I-iodobenzamide ( 123 I-IBZM) BP 6 weeks post-RYGB surgery after average 14kg weight loss, 51 suggesting that different results are unrelated to temporary early increases after surgery or differences in degree of weight loss.
However, another study showed an increase in 123 I-IBZM BP in striatum and caudate (with trend in putamen) at average 3.1 years after RYGB surgery after 31% weight loss. 52 contrast, another small study (n = 5) found a decrease in 18 Ffallypride BP in caudate at $7 weeks after RYGB/VSG surgery with average $12% weight loss. 34There was a similar trend for a decrease in 18 F-fallypride BP in caudate, putamen, and nucleus accumbens after 7-10 days of VLCD with average $3% weight loss in a larger study (n = 15), 35 suggesting that these changes may be because of weight loss or reduced energy intake rather than being specific to bariatric surgery.
To interpret these changes in dopamine 2 and 3 receptors (DRD2/3) receptor availability after weight loss needs an understanding of the effects of obesity or higher BMI itself on DRD2/3 receptor availability.In those interventional studies that examined influence of obesity at baseline, there was no difference in striatal 11 C-raclopride BP between participants without obesity/normal weight controls and pre-operative group with obesity, 32,33 nor any correlation of striatal 123 I-IBZM binding with BMI in pre-operative group with obesity. 51,52wever, in other studies, correlations between DRD2/3 receptor availability and BMI or obesity have been highly inconsistent, likely related to (i) multiple different tracers with variable characteristics, (ii) neuroanatomical localization of BP differences, (iii) severity of obesity (with some reviews suggesting inverted U-shape relationship), (iv) potential differential effects of tonic and phasic dopamine release, and (v) variable sample sizes. 58,60,61gher BMI has been associated with decreased DRD2/3 receptor availability in the ventromedial striatum using 18 F-fallypride, 59 in striatum using 11 C-raclopride 62 ; in dorsal caudate using 6-18 F-fluoro-L-m-tyrosine 63 ; and in ventral striatum, putamen and caudate using 6-18 F-fluoro-L-3,4-dihydroxyphenylalanine. 64By contrast, higher BMI has been associated with higher 18 F-fallypride BP in the dorsal and lateral striatum 59 ; in caudate 65 ; in midbrain, putamen, and ventral striatum, 66 and higher N-methyl benperidol BP in caudate. 67Greater reduction in BMI was positively associated with decrease 123 I-Nω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane, ( 123 I-FP-CIT) BP over 24 months in caudate and putamen. 68 C-4-propyl-9-hydroxynaphthoxazine ( 11 C-PHNO) is more highly selective for DRD3 over DRD2 receptors, and results have differed from the other DRD2/3 tracers.In the same study of participants without obesity (BMI 18.6-27.8 kgm 2 ), BMI was positively correlated with 11 C-PHNO BP in ventral striatum (but not caudate or putamen) but not in any striatal region with 11 C-raclopride.69 Higher BMI (range from 20.8 to 36.5 kg/m2) has also been associated with higher 11 C-PHNO BP in the dorsal striatum, 70 and across those with normal weight, overweight, and obesity in substantia nigra/ ventral tegmental area, ventral striatum, and pallidum.71 To our knowledge no studies have examined the effects of bariatric surgery or dietary weight loss on 11 C-PHNO BP.
[74][75][76] Furthermore, DRD2/3 receptors exist in either high-or low-affinity states with respect to agonists, and while agonist tracers C-FLB-457, 18 F-fallypride, 123 I-IBZM and 123 I-epidepride) do not distinguish between the two states. 77en looking at voxel-based analysis rather than averaging BP across striatal brain regions, positive correlations of BMI were found with 18 F-fallypride BP in the dorsolateral striatum including caudate and putamen, and negative correlations in the ventromedial striatum, in lean/patients with obesity. 59terpreting changes in baseline 11 C-raclopride, 123 I-IBZM, and 18 F-fallypride BP after weight loss interventions is also difficult because it is assessing post-synaptic (and potentially also pre-synaptic auto-receptors) DA receptor availability rather than the flux through the dopaminergic system.A recent review suggested that the relationship between obesity and DRD2/3 availability can be best described by a nonlinear relationship, 75 where tracer BP reflects changes in both receptor density and endogenous dopamine levels.The nonlinear relationship may be the result of an increase in tonic dopamine (sustained) levels, accompanied by a decrease in phasic dopamine (momentary) release in moderate obesity which may induce a transient, compensatory upregulation of striatal DRD2/3, resulting in a higher tracer BP in moderate obesity.However, with further progression of obesity (BMI > 40 kg/m 2 ), the lower tracer BP may reflect primarily a downregulation of DRD2/3, which can be compensatory to long-term high tonic dopamine exposure. 78e obesity intervention studies using DRD2/3 tracers examined alterations in tonic dopamine, measured during the fasting or pre-meal state without any active interventions such as presentation of food stimuli or acute food ingestion.Physiologically, dopamine is released in the striatum from midbrain neurons in response to stimuli in a phasic manner.Indeed, greater post-prandial decreases in striatal 11 Craclopride BP, indicating greater endogenous dopamine release, have been associated with greater pleasantness of the food eaten in adults without obesity. 76To our knowledge, there are no published studies of the effects of bariatric surgery or weight loss on post-prandial endogenous dopamine release.
No association between BMI and striatal dopamine transporter (DAT) availability was found using 123 I-FP-CIT, 79  tracer 80 and in participants without obesity (BMI 18-30 kg/m 2 ) using TRODAT-1 tracer. 81e study examined the effect of LCD-induced weight loss on striatal DAT using 123 I-FP-CIT, but this has not been examined after bariatric surgery.Although there was no overall change in striatal 123 I-FP-CIT binding after 1 month LCD following 6-7% weight loss, the timing of the LCD meals over the day (50% of energy intake at breakfast vs. supper) did produce differential effects on striatal 123 I-FP-CIT binding, suggesting the effect of meal timing on weight maintenance after hypocaloric diets. 53further limitation of these obesity interventional studies using tracers targeting the dopamine system is the inclusion of only females, limiting generalization of the results to both sexes. 82,83

| Serotonin system
Serotonin plays an integral role in maintaining energy homeostasis, controlling eating behavior, suppressing appetite, and promoting energy expenditure. 75,84Serotonin (5-HT) receptors are classified into seven types, 5-HT 1 through 5-HT 7 with each type having subtypes (A, B, etc.).The brain distribution of these receptors is not homogeneous nor identical.Brainstem serotonin neurons send ascending projections that terminate in a defined and organized manner in cortical, limbic, midbrain, and hindbrain regions, with brain regions expressing multiple serotonin receptors in a receptor subtype-specific fashion. 75,84e serotonin system has provided a viable target for weight control. 85Serotonin 5-HT 1B and 5-HT 2C receptors have been specifically recognized as mediators of serotonin-induced reductions in appetite. 85Systemic serotonin administration decreases food intake in humans, 86 and there is an important role for the anorexigenic hypothalamic serotonin 2C receptor (5-HT 2C R). 87 A number of serotonergic drugs, including selective serotonin reuptake inhibitors, dexfenfluramine, and 5-HT 2C R agonists, have been shown to attenuate rodent body weight gain.This effect is strongly associated with marked hypophagia and is probably mediated by the hypothalamic melanocortin system. 880][91][92][93] Additionally, sibutramine, dexfenfluramine, fluoxetine, and the 5-HT 2C R agonist chlorophenylpiperazine have all been shown to modify appetite in both lean and patients with obesity, resulting in reduced caloric intake. 85A new generation of 5-HT 2C R selective agonists have been developed such as lorcaserin which helped patients with overweight or obesity to lose weight and maintain weight loss. 85In addition, hypothalamic serotonin 2A receptor (5-HT 2A R) might have a role in the control of feeding and energy homeostasis.Positive correlations were found between BMI and 5-HT 2A R binding using 18 F-altanserin tracer in different cortical regions. 94,95Individuals with obesity had significantly higher neocortical 5-HT 2A R binding relative to lean individuals. 37On the other hand, serotonin receptor (SERT) binding was negatively correlated to BMI in cortical and subcortical regions using 11 C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile ( 11 C-DASB) PET tracer. 96 the only study of RYGB surgery, there was no effect on 18 Faltanserin BP (targeting 5-HT 2A R) despite average 25.8% weight loss. 37This was despite there being an overall increase in neocortical (averaged across orbitofrontal, medial inferior frontal, superior frontal, medial inferior and superior temporal, sensorimotor, parietal and occipital cortices) 18 F-altanserin BP in obesity (both pre-and post-RYGB surgery) than normal weight participants, and a positive correlation with BMI across participants without and with obesity.In agreement with these findings, two other studies found a positive correlation between BMI (across range from participants without and with obesity) and 18 F-altanserin binding in the neocortex (averaged across eight cortical anatomical regions of interest (aROIs): orbitofrontal, medial inferior frontal, superior frontal, superior temporal, medial inferior temporal, sensory-motor, parietal, and occipital cortices), and also individually in the above aROIs, as well as insula, hippocampus, anterior cingulate cortex and posterior cingulate cortex, in one study, 95 and in the other study in the superior temporal, medial inferior temporal, dorsolateral prefontal, and sensory-motor cortical aROIs (but not cerebellum, amygdala/hippocampus, pons, orbitofrontal cortex, ventrolateral frontal cortex, anterior cingulate gyrus, thalamus, caudate, putamen/pallidum, insula, superior medial frontal cortex, occipital cortex, or parietal cortex). 94e lack of any reduction in 18 F-altanserin BP after weight loss from RYGB surgery suggests persistence of alterations in the serotonin system in obesity, perhaps consistent with lower intra-synaptic serotonin concentrations.However, because there are no reported studies of weight loss induced by a dietary intervention on 18 Faltanserin BP, it is unclear if this is a general lack of effect from weight loss or whether RYGB surgery actually increases 18 F-altanserin BP.
The 11 C-Cimbi PET tracer is also available to target 5-HT 2A R in humans, but no studies could be found assessing influence of BMI, obesity, or interventions on its binding. 97,98 rats with diet-induced obesity from high fat diet, RYGB surgery decreased 3 H-MDL100907 binding by autoradiography (targeting 5-HT 2A R) in the nucleus accumbens (but not cortex, caudate/putamen, hippocampus, or hypothalamus) compared with sham operated rats, but no changes were seen in SERT (using (S)-[N-methyl-3 H]citalopram) or 5-HT 4 R (using 3 H-SB207145) binding restriction. 99fortunately, there are no specific tracers for the anorexigenic 5-HT 2C R. Radioligands for the other serotonin 1A and 1B (5-HT 1A/B R) and 4 (5-HT 4 R) receptors have been validated in humans, but there are no reported studies of their use in surgical or dietary weight loss interventions.
One study showed no effect of RYGB surgery on 11 C-DASB BP (targeting SERT) averaged across caudate, putamen, and thalamus, despite 25.8% weight loss. 37In agreement with this, studies have found no difference in 11 C-DASB BP between participants with and without obesity, 100  However, although LCD producing 6.5% weight loss had no overall effect on 123 I-FP-CIT BP in thalamus and hypothalamus, an increase in tracer BP in thalamus was seen when 50% of energy was consumed in breakfast (vs.supper), suggesting that thalamus SERT may be affected by timing of dietary patterns but not weight loss per se. 53

| Opioid system
There are three main families of opioid receptors (μ, ĸ, and δ) of which μ-opioid receptors (MOR) are most strongly implicated in reward processing.7][108] Administration of MOR antagonists to animals reduces food intake and body weight in rodent models, [109][110][111][112] while MOR agonists increase food intake. 113,1146][117] Recently, studies using a selective MOR antagonist GSK1521498 showed reductions in hedonic responses to sweetened dairy products and reduced energy intake, particularly of high-fat foods during ad libitum buffet meals in obesity with binge eating disorder, 118,119 and reduced attentional bias for food cues on the visual dot probe task. 120o studies observed an increase in 11 C-carfentanil BP after both RYGB/VSG surgical and VLCD dietary weight loss interventions in ventral striatum, thalamus, and orbitofrontal cortex, suggesting this is because of weight loss itself rather than changes in gut-brain axis from surgery. 33,36After bariatric surgery but not dietary interventions there were also increases in 11 C-carfentanil BP in amygdala, dorsal caudate, insula, putamen, and anterior, middle and posterior cingulate cortex, 33 whereas an increase in 11 C-carfentanil BP in temporal pole was observed after dietary but not surgical interventions. 36e anatomical differences in the increases in 11 C-carfentanil BP between surgical and dietary interventions may be a result of the greater weight loss in the former (23.3% vs. 16.1%,respectively) as well as the time since start of intervention (6.0 vs. 3.7 months, respectively).Moreover, the surgical intervention study was much larger than the dietary study (16 vs. 7 participants), and there were differences in participant sex (all female in surgical, all male in dietary study), prevalence of T2DM (38% vs 0%), and nutritional state (fed in surgical, fasted in dietary study) which further impairs the comparison between these two studies. 36ese results suggest that weight loss by surgical or dietary interventions is normalizing the lower 11 C-carfentanil BP seen in obesity (pre-intervention vs. participants without obesity) in ventral striatum, dorsal caudate, putamen, thalamus, amygdala, insula, posterior cingulate cortex and orbitofrontal cortex (average and individual regions of interests [ROIs]), 33 thalamus, amygdala, temporal pole, and prefrontal cortex. 36These cross-sectional findings in obesity are supported by others that have found lower 11 C-carfentanil BP in ventral striatum, dorsal caudate, putamen, insula, amygdala, thalamus, orbitofrontal cortex, and posterior cingulate cortex. 61ere are no PET studies investigate ĸand δ-opioid receptors in human obesity or interventions.Preliminary data from transgenic knockout models suggest that mice lacking some of these receptors are resistant to high fat diet-induced obesity, suggesting a role of these receptors in controlling energy metabolism. 121,122][125][126]

| Noradrenaline system
8][129] Noradrenaline also plays an important role in energy balance. 128,129In rodent studies, exogenous noradrenaline can elicit or reduce feeding, depending on the site of infusion (lateral hypothalamus stimulates feeding; perifornical hypothalamus inhibits feeding; lesions of the ascending ventral noradrenergic bundle increases food intake and produces obesity, whereas interruption of projections of the dorsal noradrenergic bundle lowers body weight) and the relative balance of post-synaptic α2-adrenoceptors (stimulate food intake) and α1-adrenoceptors (inhibit food intake). 130,131These two adrenoceptor subtypes are localized in the hypothalamic paraventricular nucleus and appear to be organized in an antagonistic fashion. 132[135] In the only study, there was no effect of LCD intervention on 11 C-methylreboxetine ( 11 C-MRB) BP (targeting NAT) after 3.7% weight loss over 6 months. 47However, the weight loss was minimal, and the participants still had obesity after the intervention with average BMI 41.0 kg/m 2 .However, greater weight loss after LCD was associated with a greater increase in 11 C-MRB BP in the insula and hippocampus, but the role of noradrenergic signaling on energy balance in these brain regions is unclear.Furthermore, lower 11 C-MRB BP at baseline was associated with greater weight loss after LCD in insula and hippocampus, and also putamen, midbrain, and dorsolateral prefrontal cortex. 47recent study that investigated the effect of RYGB surgery on NAT observed a higher 11 C-MRB BP in hypothalamus at baseline was associated with greater weight loss 6 months post-RYGB surgery, a brain region responsible for appetite control and homeostasis.Moreover, reductions in BMI after RYGB surgery was associated with reductions in NAT availability in the dorsolateral prefrontal cortex and a general tendency towards reduced NAT throughout the brain.136 However, these preliminary findings need confirmation with larger cohorts.
While this direction of change in 11 C-MRB BP with weight loss has been supported by cross-sectional studies in obesity, the exact brain regions involved have differed: (i) in lean-to-participants with severe obesity, higher BMI was associated with lower 11 C-MRB BP in the hypothalamus, 137 whereas (ii) participants with class I obesity (mean BMI 34.7 kg/m 2 ) had lower 11 C-MRB BP in the thalamus but not hypothalamus compared to lean participants. 138However, these results have not been replicated in more severe class II and class III obesity (BMI > 35 kg/m 2 ). 139,140 therefore remains uncertain if impaired NAT availability is a definite feature of obesity and if it is playing any pathogenic role in overeating behavior.A number of anti-obesity drugs have targeted the noradrenaline system though rarely used clinically because of adverse effect profiles particularly due to peripheral monoamine release such as increased heart rate and blood pressure.Their mechanisms of action are complex though, because they often affect multiple monoamine neurotransmitter systems, for example, sibutramine reduces reuptake of noradrenaline and also serotonin and dopamine; phentermine and amphetamine stimulate monoamine release from neurons via trace-amine associated receptor 1 (TAAR1) receptor including noradrenaline and, to a lesser extent, serotonin and dopamine. 128The potential reduced NAT uptake in obesity and its increase with dietary weight loss could therefore represent a counter-regulatory response to obesity rather than a pathogenic cause.

| Fatty acid uptake
The hypothalamic metabolism of fatty acids can modify feeding behavior and has been proposed to function as a biochemical sensor for nutrient availability that in turn exerts negative feedback on nutrient intake. 87,141,142The mechanisms by which hypothalamic longchain fatty acid (acyl-CoAs) concentrations can be increased are enhanced esterification of circulating or central nervous system lipids 143,144 and/or by the local inhibition of lipid oxidation. 1451][152] Moreover, hypothalamic injury can occur in response to increased dietary fat very early (1-3 days) even before the development of obesity in rodents, 153 and the normalization of hypothalamic lipid sensing has been linked to normalization of energy and glucose homeostasis in rats. 154 addition, free fatty acids induce insulin and leptin resistance which may cause neuronal damage through inflammation including the hypothalamus and so further affect control of energy balance. 151,155,156Hypothalamic overexpression of a constitutively active IKKβ isoform (which is activated by saturated fatty acids and oxidative stress) can reduce both insulin and leptin signaling 151 ; conversely, intracerebroventricular administration of an IKKβ inhibitor reverses high fat diet-induced hypothalamic insulin resistance, 157 and neuronspecific deletion of IKKβ maintains leptin and insulin sensitivity in high fat diet fed mice. 151These control processes are difficult to examine in humans in vivo, and so most data in this regard have only been demonstrated in animals. 146,148,158One key unresolved question regarding the effect of fatty acids in the brain is the nature of the cell types and if there are other brain regions involved in the response.
Both PET studies of dietary and surgical weight loss interventions showed higher brain 18 F-fluoro-6-thia-heptadecanoic acid ( 18 F-FTHA) BP (which measures total FA uptake and is found mostly in triglycerides in brain lipids) globally and in cortical regions in obesity (pre-intervention vs. participants without obesity), 46,49 as well in subcortical and hypothalamus in one study. 46However, only the dietary intervention study observed a reversal with weight loss with a decrease in 18 F-FTHA BP globally and regionally in cortical, subcortical, and hypothalamus 1.5 months after VLCD with 11.1% weight loss. 46However, 18 F-FTHA BP was unchanged 6 months post-RYGB/ VSG surgery in cortical regions despite greater 22.6% weight loss to a similar BMI to the post-VLCD study. 49Unfortunately, this surgical study did not include the hypothalamus as a region of interest.
Instead, they measured the ratio of hypothalamic-to-amygdala signal intensity (using fluid-attenuated inversion recovery, FLAIR-MRI) which has been previously shown to reflect hypothalamic inflammation, 153 but this did not differ between participants with obesity and controls at baseline nor change after surgery. 49The authors mentioned this may be a result of methodological limitations because of slice thickness of 5 mm.
Thus, these differences between the two studies in changes in 18 F-FTHA BP in cortical regions are unlikely to be explained by magnitude of weight loss, but there could be adaptation to weight loss over time, or else surgical intervention increases 18 F-FTHA BP through uncertain mechanisms.The authors hypothesized that surgical stress may be a factor, but this is unlikely to be important at 6 months post-surgery. 49 C-palmitate measures non-oxidative fatty acid uptake and is found mostly in phospholipids in brain lipids, with only trace amounts in triglycerides and fatty acids.Interestingly, 11 C-palmitate BP did not change after weight loss from VLCD dietary intervention, suggesting that the greater 18 F-FTHA BP in obesity, and decrease in 18 F-FTHA BP after VLCD, is primarily because of decreases in oxidative fatty acids, which are those associated with inflammation and neuronal damage. 466 | Regional cerebral blood flow Regional cerebral blood flow can be used to assess local neuronal activity at rest and/or in response to interventions because of the neurovascular coupling that results in local vasodilation.rCBF can be measured by PET imaging with 15 O-water ( 15 O-H 2 O) 12 and by magnetic resonance imaging using arterial spin labeling (ASL). 159e small longitudinal study with only males with obesity (n = 4) showed no change in rCBF using 15 O-H 2 O PET averaged across the whole brain after 3 weeks of total fasting. 43Only one larger study (n = 11) assessed the effect of RYGB surgery on rCBF, in this case using ASL. 50After RYGB, there was increased rCBF in the whole brain, white and gray matter, and individually within caudate, putamen, pallidum, thalamus, amygdala, hippocampus, hypothalamus, frontal, parietal, temporal and occipital lobes, and cerebellum, during normoglycemia and in most of these brain regions during hypoglycemia. 50This suggests differential global changes in neuronal activity after weight loss from RYGB surgery than extreme dietary restriction.
However, interpretation of these findings is complicated by (i) neither study including normal weight participants (unclear what direction of change would be expected to normalize obesity-associated changes in rCBF), (ii) global effects raise the possibility of non-specific effects after RYGB surgery, (iii) prolonged fasting was a dietary intervention that is an unusual treatment, (iv) samples sizes were small, and (v) these two studies used different methods to assess rCBF.
Furthermore, another longitudinal study using ASL found no change in rCBF at 6 months after RYGB surgery versus preoperatively (n = 9) nor any difference in rCBF at baseline compared to controls without obesity (n = 8), in any regional brain network defined using resting state functional MRI (dorsal default mode, ventral default mode, auditory, basal ganglia, left or right executive control, language, precuneus, sensorimotor network, primary visual, visuospatial, higher visual, anterior salience, and posterior salience networks). 160ree cross-sectional studies used 15 O-H 2 O PET to compare successful dieters with non-dieters with obesity (and sometimes also those who never had obesity) to measure rCBF responses to taste or intake of a liquid meal (Ensure) but with overlapping datasets. 44,45,48wever, none of these studies just compared rCBF between groups when fasted.
In the insula (a brain region that includes the taste cortex), increase in rCBF after taste (but not after food intake) relative to fasting was higher in both non-dieters with obesity and successful dieters (but similar between groups) than those who have never had obesity, suggesting a persistence of potentially pathogenic abnormality from obesity even after dietary-induced weight loss. 44,45,48w studies have examined the effects of obesity surgery on brain responses to sweet taste using fMRI. 161,162Interestingly, one study found a reduction in blood oxygen level dependent (BOLD) signal to chocolate milk taste (sweet, high fat) in the insula (which includes gustatory cortex) after RYGB surgery. 161Furthermore, this was attenuated by acute administration of the glucagon-like peptide-1 (GLP-1) analog Exendin (9-39), indicating a potential role for the increased plasma GLP-1 after RYGB in these changes of sweet/fat taste responsivity. 163,164 the hippocampus and parahippocampal gyrus (regions involved in memory and learning), rCBF after food intake decreased more in both non-dieters with obesity and successful dieters (but similar between groups) than those who have never had obesity, again suggesting a persistence of response from obesity even after dietaryinduced weight loss, 44 but this was only replicated for non-dieters with obesity in a reanalysis of this study. 48 contrast, in the amygdala and posterior cingulate cortex, a greater increase in rCBF after food intake was seen in non-dieters with obesity than both successful dieters and participants who never had obesity, suggesting a reversible consequence of obesity that normalizes after weight loss. 44However, these findings were not replicated in the other two studies. 45,48 contrast, more consistent results were found in the dorsal and dorsolateral pre-frontal cortex (a region involved in top-down inhibitory control 165 ), with a greater decrease in rCBF after food intake in non-dieters with obesity than both successful dieters and participants who never had obesity. 45,489][170] Reduced prefrontal cortex function in obesity when fasted or after food intake may contribute to a lack of inhibition of overeating in obesity, 171 and impaired cessation of a feeding episode, as the dorsal prefrontal cortex has efferent inhibitory projections to the central orexigenic system. 172[175] Although not always replicated or regions were not re-examined, rCBF after food intake (vs.fasted) was greater in putamen, and lower in orbitofrontal cortex and occipital lobe in successful dieters (but not those who never had obesity) than non-dieters with obesity, 45,48 whereas rCBF after food intake was greater in cerebellum, and lower in STG and MTG, in successful dieters than those who never had obesity. 45,48veral factors may contribute to differences between these 15 O-H 2 O PET studies that investigate response to food, including sex ratio (both sexes, 44 only females 45,48 ), different pre-processing steps, 45,48 and statistical analyses (single-level, fixed-effect analysis 44 ; secondlevel, random-effects re-analysis 48,166 ).

| Brain glucose uptake
The brain uses glucose as a primary fuel for energy generation.Glucose enters the brain by facilitated diffusion across the blood-brain barrier.BGU can be used to assess local neuronal activity by PET imaging with 18 F-FDG tracer, 176 though glucose transport might also be altered during changes in non-neuronal glucose uptake (e.g.astrocytes, glia cells) 177 and non-specific changes in cerebral glucose metabolism and/or insulin resistance and plasma glucose concentrations. 178,179Several studies investigated BGU post-bariatric surgery [38][39][40][41]50 or post-dietary intervention, 42,43 but the findings are sometimes difficult to compare because of methodological differences, especially around nutritional and metabolic state.
In one cross-sectional study, BGU was measured in response to food intake post-RYGB surgery compared with adults with and without obesity, 38 whereas in longitudinal studies, one study measured BGU in response to hyperinsulinemic normoglycemic or hypoglycemic clamps post-RYGB surgery, 50 and two studies during hyperinsulinemia normoglycemic clamp post-RYGB/VSG surgery. 39,41During hyperinsulinemia normoglycemic clamps, there was a decrease in whole brain BGU post-RYGB surgery 50 and post-RYGB/VSG surgery in one of the two studies which included patients with T2DM, 39 but not the other without patients with T2DM, despite similar weight loss. 41This may be consistent with the reductions in insulin resistance seen after bariatric surgery, though none of these studies correlated changes in BGU with changes in insulin resistance.
A cross-sectional study of response to food intake post-RYGB surgery found greater increase in BGU in the hypothalamus, pituitary, and medial orbitofrontal cortex compared with controls with and without obesity, and greater decrease in BGU in dorsolateral prefrontal cortex and default mode network (posterior cingulate gyrus, precuneus cortex, cuneus, angular gyrus, superior temporal gyrus posterior, middle temporal gyrus posterior, occipital pole, and parietal lobule) compared with controls with and without obesity. 38Surprisingly, these changes post-RYGB surgery appeared to be largely independent of gut hormone release as they persisted after administration of the somatostatin analog Octreotide that suppresses satiety gut hormones such as peptide YY (PYY) and GLP-1.
One longitudinal study of RYGB surgery examined BGU without a hyperinsulinemic clamp but did not report the nutritional state of participants. 40The two dietary intervention studies only measured BGU during the fasting state 42,43 ; however, one was after 3 weeks of total fasting without any task, 43 whereas the other was while viewing high-energy, palatable food pictures. 42 studies were found investigating the effect of VSG alone (always combined with RYGB surgery as one group), gastric banding, or biliopancreatic diversion for obesity on neurotransmitter systems or brain metabolism, nor the effects of any obesity surgery on the noradrenaline system.

| Correlations of PET/SPECT findings with clinical outcomes
,52 For example, looking at baseline PET results correlating with weight loss, (i) higher BP in neocortex for 5HT 2A R but not serotonin transporter was correlated with greater weight loss post-RYGB surgery 37 ; (ii) a greater post-prandial increase in MOR availability in temporal pole was correlated with less weight loss after VLCD intervention 36 ; (iii) no correlation was observed between baseline BGU and weight loss post-RYGB/VSG surgery 39 ; while (iv) higher BP for NAT in putamen, hippocampus, midbrain, insula, and dorsolateral prefrontal cortex was correlated with less weight loss post-LCD intervention. 47en looking at correlation of changes in PET/SPECT findings with weight loss: (i) despite no overall changes in BP after the intervention, a smaller increase in neocortex 5HT 2A R availability, and in caudate, putamen, and thalamus for serotonin transporter, was correlated with greater weight loss post-RYGB 37 ; (ii) no correlations between loss of weight nor fat mass and change in DRD2/3 receptor availability were seen post-RYGB despite changes in BP being seen after surgery 52 ; (iii) a greater increase in NAT in hippocampus and insula was associated with greater weight loss post-LCD, despite no overall change in transporter post-dietary intervention 47 ; while (iv) changes in BGU did not correlate with loss of weight or fat post-LCD. 42hen looking at correlation of baseline PET/SPECT findings with changes in glycemic control, two studies of RYGB/VSG surgery for obesity (with 32-38% having T2DM) found that: (i) higher whole brain BGU (during insulin stimulation) was correlated with less improvement in fasting plasma glucose (FPG) at 3 years, perhaps indicative of better insulin sensitivity at baseline with a floor effect 39 ; and similarly (ii) higher whole brain free fatty acid (FFA) uptake was correlated with less improvement in FPG at 2 years. 49en looking at correlation of changes in PET/SPECT findings with changes in glycemic control, (i) there was no correlation between increase in DRD2/3 availability ( 123 I-IBZM BP) in striatum with decrease in FPG at 3 years post-RYGB surgery for obesity (with unknown number having T2DM at baseline) 52 ; while (ii) greater reduction in DRD2/3 availability ( 18 F-fallypride BP) in caudate, putamen, and substantial nigra correlated with greater decrease in FPG 10 days post-VLCD for obesity (only 7% with T2DM). 359 | Correlations of PET/SPECT findings with mechanistic measures Bariatric surgery involves a profound anatomical change to the gastrointestinal tract, which causes a more rapid delivery of nutrients to the distal small bowel. 3,180As a result, after RYGB and VSG surgery, gut adaptation facilitates an exaggerated, early post-prandial rise in peripheral anorexigenic gut hormones including PYY and GLP-1, and a reduced post-weight loss rise in fasting and/or post-prandial plasma concentrations of the potentially orexigenic stomach-derived hormone ghrelin, likely as a result of the exclusion of food from the stomach (though the majority of studies have examined total rather than acyl ghrelin), that occurs within days after surgery and persists long term. 3,181These appetitive gut hormones have receptors in the peripheral and central nervous systems forming a gut-brain hormonal axis.Therefore, these obesity surgeries promote weight loss by reducing appetite, partly mediated by changes in appetitive gastrointestinal hormone secretion. 3,5rthermore, the effects of RYGB and VSG surgery on gut hormones are different from the effects of dietary intervention. 181Fasting plasma total ghrelin decreased more after RYGB surgery than matched weight loss from VLCD, whereas post-oral glucose plasma total ghrelin was unchanged after RYGB surgery, but increased after matched weight loss from diet alone. 182,183Post-oral glucose plasma GLP-1 increased after RYGB surgery for obesity with T2DM, but not after matched weight loss from LCD. 184 In addition, despite similar weight loss, fasting and post-prandial acyl ghrelin may decrease more after VSG than RYGB surgery, while post-prandial plasma PYY 3-36 and active GLP-1 may increase more after RYGB than VSG surgery. 185servations of differences in PET/SPECT outcomes between surgical and dietary interventions implicate some of these mechanistic changes in gut anatomy-physiology after surgery compared with dietary intervention, 46,49 38 This was despite these regions being those showing differences in post-prandial BGU in patients post-RYGB surgery compared to participants with obesity or normal weight controls, suggesting that the exaggerated postprandial GLP-1 and PYY responses after RYGB surgery were not responsible for changes in regional BGU, though sample size was small for the post-RYGB group (n = 9).This is in contrast to an fMRI study of food cue reactivity, where acute suppression of postprandial plasma GLP-1 and PYY with Octreotide increased food picture appeal and cue reactivity across nucleus accumbens, anterior insula, amygdala, and caudate post-RYGB surgery (but not gastric banding), while the greater the suppression of plasma PYY and GLP-1, the greater the increase in food cue reactivity across both post-surgical groups.

| Correlations of PET/SPECT measures with mood
Most longitudinal studies did not measure changes in mood, 35,38- 46,48-53 and some found no change in mood post-RYGB or VSG surgery 33,34,37 or LCD 47 or VLCD, 36 whereas one study showed lower depression post-RYGB surgery that was associated with a reduction in DRD2/3 availability ( 11 C-raclopride BP) across ventral striatum, caudate, and putamen, though no direct correlation was performed. 32provements in mood are often seen after bariatric surgery, 187,188 and so may be a cofounding factor when interpreting PET findings.

| Interactions between neurotransmitter systems
Furthermore, published studies have generally examined neurotransmitter systems and brain regions in isolation and have not examined how the neurotransmitter systems interact with each other and how they work on a systemic level such as in the brain reward system.Only two longitudinal studies included multiple tracers looking at neurotransmitter systems in the same participants, but none looked at correlations between changes in the different tracer BPs as a result of the intervention.There were increases in 11 C-carfentanil BP (MOR) in ventral and dorsal striatum, but no changes in 11 C-raclopride BP (DRD2/3) in these regions, in a longitudinal study of RYGB/VSG surgery, 33 that normalized the reductions in 11 C-carfentanil BP seen in obesity (vs.without obesity), with no effect of obesity for 11 C-raclopride BP. 33,61 Examining dopamine and serotonin transporter (both FP-CIT) in a longitudinal study of 4 weeks LCD found no changes in former and changes in serotonin transporter BP in thalamus, the direction of which depended on distribution of energy intake over the day. 53teraction of dopaminergic/noradrenergic systems with opioid and serotonin systems is demonstrated from PET studies of effects of oral administration of amphetamine, which increases dopaminergic and noradrenergic systems (via dopamine and noradrenaline transporter inhibition, vesicular monoamine transporter 2 [VMAT-2] inhibition, and monoamine oxidase activity inhibition). 97,190,191Amphetamine administration released endogenous beta-endorphin and serotonin as measured by reductions in BP for 11 C-carfentanil (MOR agonist) in putamen, caudate, nucleus accumbens, frontal cortex, anterior cingulate cortex, insula, and thalamus, 190,191 and by reductions in 11 C-CIMBI-36 (5HT-2A receptor agonist) in frontal, parietal, temporal, and occipital cortex. 97However, while blunting of these effects of amphetamine have been reported in gambling disorder and abstinent alcohol dependence, 192,193 and depression, 194 to our knowledge they have not been studied in obesity or following its treatment. [198][199][200][201][202][203]

| Limitations
Although it was hoped to conduct a meta-analysis, this was not possible because of several limitations from the available studies: (i) combined groups composed of patients who underwent different surgeries which have differing effects on gut anatomy and physiology, (ii) different times since surgery or start of dietary intervention, (iii) small number of included manuscripts for each brain neurotransmitters system or metabolite, let alone the specific PET/SPECT tracer used, (iv) different nutritional and metabolic states used between studies, (v) different ROIs used in particular studies further decreasing the number of studies that could be included in a meta-analysis, and (vi) very few studies reported spatial co-ordinates from whole brain analysis precluding combination of results using an ALE analysis (using GingerALE software, http://brainmap.org).In addition, this systematic review did not focus on the different analytical models used in quantification in PET/SPECT data.

| Recommendations
There are notable gaps in the literature.We offer the following recommendations to further accelerate the field's understanding of the effect of obesity surgery on neurotransmitter systems and brain metabolism and to determine the potential of these surgeries for the clinical treatment of obesity: ix.Although it would be best to have a double-blind, randomized control study design in studies involving surgical procedures, this is difficult because of logistical and ethical issues.
x.Some of the reviewed studies only included one sampling time point (if any) for gastrointestinal hormones, usually in the fasted state.It is of interest to determine how these appetitive hormones are affected in the postprandial state.Therefore, future studies should sample before and after a meal to capture the gastrointestinal hormone response profile.
xi. Reporting data using whole brain analysis or/and standardization of ROIs so meta-analysis can be easily performed.
xii.Assessment of interactions between neurotransmitter systems and their association with changes in functional MRI measures, for example, food cue reactivity or resting state functional connectivity, aided by dual PET/MRI scanners now being available.

| Conclusions
There is an increase in MOR BP post-RYGB/VSG surgery and VLCD intervention, suggesting changes in the opioid system may be secondary to weight loss or reduced energy intake rather than changes in gut-brain axis from surgery.It also suggests that weight loss normalizes the lower 11  The small number of studies with each tracer and lack of control groups made definitive conclusions challenging.Variability in methodology used, duration since intervention, amount of weight loss, nutritional status, methods of statistical analysis, small sample size, predominantly females included, and the use of combined surgical groups also limit conclusions.These limitations need to be addressed in future studies examining the effects of different bariatric surgeries in order to fully understand the role for changes in neurotransmitter systems or brain metabolism involved in changing eating behavior.
This will help us understand the mechanisms that cause weight loss after surgical interventions and in return help tailor treatments for the patient and identify potential therapeutic targets for non-surgical weight loss in obesity.
IntroductionIn many parts of the world, obesity has reached pandemic proportions; the number of deaths because of obesity-related health issues is rising at an unprecedented pace, and controlling obesity remains a daunting challenge.The obesity epidemic has tripled since 1975; i. Longitudinal and cross-sectional human studies.ii.Studies published in English.iii.Articles published between January 1980 and April 2021.iv.Studies conducted on adolescents or adults aged 16 years and older, of either sex.v. Participants in the intervention group should be diagnosed with overweight (body mass index, BMI > 25 kg/m 2 ) or obesity with BMI > 30 kg/m 2 .vi. Assessments of obesity surgery (RYGB, VSG, one anastomosis gastric bypass, gastric banding, vertical band gastroplasty, biliarypancreatic diversion, and gastric balloon) and dietary interventions.
whereas three studies used SPECT scans. 51-533.2 | Study summary 3.2.1 | PET/SPECT tracers A complete description of all PET/SPECT tracers is available in S1 Results.Radioactive tracers used to investigate neurotransmitter systems are illustrated in Figure 2. Radioactive tracers used to investigate brain metabolism are illustrated in Figure 3.

F
I G U R E 3 Summary of radioactive tracers used to investigate brain metabolism.Number in brackets indicates number of studies.F I G U R E 2 Summary of radioactive tracers used to investigate neurotransmitter systems.Number in brackets indicates number of studies.T A B L E 1 Study summaries.

4. 10 |
Correlations of PET/SPECT findings with behavioral measuresSimilarly, very few studies have assessed correlations between PET/SPECT findings and changes in eating behavior precluding any definitive conclusions of brain changes with behaviors leading to weight loss: (i) the decrease in state (but not trait) food craving was positively correlated to the increase in striatal DRD2/3 availability ( 123 I-IBZM BP) 3 years post-RYGB 52 ; (ii) changes in post-prandial 5-HT 2A R and SERT availability did not correlate with increased postprandial satiety post-RYGB surgery, though this is unsurprising as overall there was no change in the PET outcomes.37None of the studies included in this systematic review correlated change in PET measures with change in food liking or wanting score, changing in taste function, nausea, dumping syndrome, or food aversion.

11 C
-raclopride and11 C-carfentanil BP were reported in the ventral striatum and caudate but not in the putamen in lean participants, and in severe obesity the correlation in the ventral striatum was attenuated, suggesting aberrant mesolimbic dopamine-opiate interaction in obesity.195However, it has not yet been reported whether surgical or dietary interventions for obesity normalize this correlation in the ventral striatum.

i.
Enrolment of larger sample sizes with greater representation across age and sex, particularly studies involving young adults and males.ii.Subgrouping according to the type of the surgery and classification of participants according to BMI. iii.Including a control group for effects of weight loss or dietary/ psychological advice.iv.Examine the effect of VSG surgery, because 20% of the bariatric surgery studies included in this systematic review had mixed groups post-RYGB/VSG, and no studies examined VSG alone, nor included gastric banding or biliopancreatic diversion surgery.v. Careful consideration regarding the control groups used (e.g., controlling for BMI, T2DM, age, mood, and medication).vi.Simultaneous assessment of multiple biomarkers (e.g., mechanistic outcome) to determine the additive value of each marker in the clinical assessment of brain function.vii.Address mediators of the effect of the intervention on brain function (e.g., hormonal change and behavior change).viii.Correlate change in PET/SPECT measures with change in food liking or wanting score, change in taste function, nausea, dumping syndrome or food aversion.
C-carfentanil BP seen in obesity.BGU both globally and regionally usually decreased after bariatric surgery, and was also seen with LCD and prolonged fasting, again suggesting the effects are because of weight loss itself or reduced energy intake.The findings are sometimes difficult to compare because of methodological differences, especially around nutritional and metabolic state.Results from the studies examining associations of PET/SPECT findings with clinical outcomes did not offer reproducible evidence that their changes predict weight loss or improvements in glucose metabolism because of the paucity of studies with each intervention, tracer, and neurotransmitter system, and lack of consistency between overall effects of intervention on neuroimaging outcomes and correlations.A limited number of studies have assessed correlations between PET/SPECT findings and potential mediators or behavioral outcomes, again meaning that definitive conclusions cannot be made.Most longitudinal studies did not measure changes in mood which may be a cofounding factor when interpreting PET/SPECT findings.None of the studies included in this systematic review correlated changes in PET/SPECT measures with changes in food liking or wanting score, taste function, nausea, dumping syndrome or food aversion.