Jetro J. Tuulari

Obesity Is Associated with Decreased μ-Opioid But Unaltered Dopamine D2 Receptor Availability in the Brain

Neurochemical pathways involved in pathological overeating and obesity are poorly understood. Although previous studies have shown increased μ-opioid receptor (MOR) and decreased dopamine D2 receptor (D2R) availability in addictive disorders, the role that these systems play in human obesity still remains unclear. We studied 13 morbidly obese women [mean body mass index (BMI), 42 kg/m2] and 14 nonobese age-matched women, and measured brain MOR and D2R availability using PET with selective radioligands [11C]carfentanil and [11C]raclopride, respectively. We also used quantitative meta-analytic techniques to pool previous evidence on the effects of obesity on altered D2R availability. Morbidly obese subjects had significantly lower MOR availability than control subjects in brain regions relevant for reward processing, including ventral striatum, insula, and thalamus. Moreover, in these areas, BMI correlated negatively with MOR availability. Striatal MOR availability was also negatively associated with self-reported food addiction and restrained eating patterns. There were no significant differences in D2R availability between obese and nonobese subjects in any brain region. Meta-analysis confirmed that current evidence for altered D2R availability in obesity is only modest. Obesity appears to have unique neurobiological underpinnings in the reward circuit, whereby it is more similar to opioid addiction than to other addictive disorders. The opioid system modulates motivation and reward processing, and low μ-opioid availability may promote overeating to compensate decreased hedonic responses in this system. Behavioral and pharmacological strategies for recovering opioidergic function might thus be critical to curb the obesity epidemic.

Obesity is associated with white matter atrophy: A combined diffusion tensor imaging and voxel‐based morphometric study

Little is known about the mechanisms by which obesity influences brain structure. In this study, the obesity‐related changes in brain white and gray matter integrity were examined.

Neural Circuits for Cognitive Appetite Control in Healthy and Obese Individuals: An fMRI Study

The mere sight of foods may activate the brain’s reward circuitry, and humans often experience difficulties in inhibiting urges to eat upon encountering visual food signals. Imbalance between the reward circuit and those supporting inhibitory control may underlie obesity, yet brain circuits supporting volitional control of appetite and their possible dysfunction that can lead to obesity remain poorly specified. Here we delineated the brain basis of volitional appetite control in healthy and obese individuals with functional magnetic resonance imaging (fMRI). Twenty-seven morbidly obese women (mean BMI = 41.4) and fourteen age-matched normal-weight women (mean BMI = 22.6) were scanned with 1.5 Tesla fMRI while viewing food pictures. They were instructed to inhibit their urge to eat the foods, view the stimuli passively or imagine eating the foods. Across all subjects, a frontal cortical control circuit was activated during appetite inhibition versus passive viewing of the foods. Inhibition minus imagined eating (appetite control) activated bilateral precunei and parietal cortices and frontal regions spanning anterior cingulate and superior medial frontal cortices. During appetite control, obese subjects had lower responses in the medial frontal, middle cingulate and dorsal caudate nuclei. Functional connectivity of the control circuit was increased in morbidly obese versus control subjects during appetite control, which might reflect impaired integrative and executive function in obesity.

Weight loss after bariatric surgery normalizes brain opioid receptors in morbid obesity.

Positron emission tomography (PET) studies suggest opioidergic system dysfunction in morbid obesity, while evidence for the role of the dopaminergic system is less consistent. Whether opioid dysfunction represents a state or trait in obesity remains unresolved, but could be assessed in obese subjects undergoing weight loss. Here we measured brain μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) availability in 16 morbidly obese women twice—before and 6 months after bariatric surgery—using PET with [11C]carfentanil and [11C]raclopride. Data were compared with those from 14 lean control subjects. Receptor-binding potentials (BPND) were compared between the groups and between the pre- and postoperative scans among the obese subjects. Brain MOR availability was initially lower among obese subjects, but weight loss (mean=26.1 kg, s.d.=7.6 kg) reversed this and resulted in ~23% higher MOR availability in the postoperative versus preoperative scan. Changes were observed in areas implicated in reward processing, including ventral striatum, insula, amygdala and thalamus (Ps<0.005). Weight loss did not influence D2R availability in any brain region. Taken together, the endogenous opioid system plays an important role in the pathophysiology of human obesity. Because bariatric surgery and concomitant weight loss recover downregulated MOR availability, lowered MOR availability is associated with an obese phenotype and may mediate excessive energy uptake. Our results highlight that understanding the opioidergic contribution to overeating is critical for developing new treatments for obesity.

The Effects of Bariatric Surgery on Pancreatic Lipid Metabolism and Blood Flow

CONTEXT Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN This was a longitudinal study. SETTING The study was conducted in a clinical research center. PARTICIPANTS This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of β-cell function, glucose tolerance, and insulin sensitivity. RESULTS Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and β-cell function. CONCLUSIONS Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.

Aberrant mesolimbic dopamine-opiate interaction in obesity.

Dopamine and opioid neurotransmitter systems share many functions such as regulation of reward and pleasure. μ-Opioid receptors (MOR) modulate the mesolimbic dopamine system in ventral tegmental area and striatum, key areas implicated in reward. We hypothesized that dopamine and opioid receptor availabilities correlate in vivo and that this correlation is altered in obesity, a disease with altered reward processing. Twenty lean females (mean BMI 22) and 25 non-binge eating morbidly obese females (mean BMI 41) underwent two positron emission tomography scans with [(11)C]carfentanil and [(11)C]raclopride to measure the MOR and dopamine D2 receptor (DRD2) availability, respectively. In lean subjects, the MOR and DRD2 availabilities were positively associated in the ventral striatum (r=0.62, p=0.003) and dorsal caudate nucleus (r=0.62, p=0.004). Moreover, DRD2 availability in the ventral striatum was associated with MOR availability in other regions of the reward circuitry, particularly in the ventral tegmental area. In morbidly obese subjects, this receptor interaction was significantly weaker in ventral striatum but unaltered in the caudate nucleus. Finally, the association between DRD2 availability in the ventral striatum and MOR availability in the ventral tegmental area was abolished in the morbidly obese. The study demonstrates a link between DRD2 and MOR availabilities in living human brain. This interaction is selectively disrupted in mesolimbic dopamine system in morbid obesity. We propose that interaction between the dopamine and opioid systems is a prerequisite for normal reward processing and that disrupted cross-talk may underlie altered reward processing in obesity.

Weight Loss After Bariatric Surgery Reverses Insulin-Induced Increases in Brain Glucose Metabolism of the Morbidly Obese

Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery.

Bariatric Surgery Induces White and Grey Matter Density Recovery in the Morbidly Obese: A Voxel-Based Morphometric Study

Obesity is associated with lowered brains grey (GM) and white matter (WM) density as measured by voxel‐based morphometry (VBM). Nevertheless, it remains unknown whether obesity has a causal influence on cerebral atrophy. We recruited 47 morbidly obese subjects (mean BMI = 42.2, SD = 4.0, 42 females and five males) eligible for bariatric surgery and 29 non‐obese subjects (mean BMI = 23.2, SD = 2.8, 23 females and six males) served as controls. Baseline scans were acquired with T1‐weighted magnetic resonance imaging (MRI) at 1.5 Tesla; obese participants were scanned again six months after the surgery. Local GM and WM densities were quantified using VBM. Full‐volume analyses were used for comparing baseline between‐group differences as well as the effects of surgery‐induced weight loss in the morbidly obese. Metabolic variables were used in linear models to predict WM and GM densities. Obese subjects had initially lower GM densities in widespread cortical areas including frontal, parietal, and temporal regions as well as insulae. Lower WM densities were observed throughout the WM. Bariatric surgery and concomitant weight loss resulted in global increase in WM density. Grey matter increase was limited to occipital and inferior temporal regions. Metabolic variables were associated with brain densities. We conclude that weight loss results in global recovery of WM as well as local recovery of grey matter densities. These changes likely reflect improved brain tissue integrity. Hum Brain Mapp 37:3745–3756, 2016.

Opioid Release after High-Intensity Interval Training in Healthy Human Subjects

Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant effective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral μ-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [11C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the μ-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise.

Bariatric Surgery Induces White and Grey Matter Density Recovery in the Morbidly Obese

Obesity is associated with lowered brains grey (GM) and white matter (WM) density as measured by voxel‐based morphometry (VBM). Nevertheless, it remains unknown whether obesity has a causal influence on cerebral atrophy. We recruited 47 morbidly obese subjects (mean BMI = 42.2, SD = 4.0, 42 females and five males) eligible for bariatric surgery and 29 non‐obese subjects (mean BMI = 23.2, SD = 2.8, 23 females and six males) served as controls. Baseline scans were acquired with T1‐weighted magnetic resonance imaging (MRI) at 1.5 Tesla; obese participants were scanned again six months after the surgery. Local GM and WM densities were quantified using VBM. Full‐volume analyses were used for comparing baseline between‐group differences as well as the effects of surgery‐induced weight loss in the morbidly obese. Metabolic variables were used in linear models to predict WM and GM densities. Obese subjects had initially lower GM densities in widespread cortical areas including frontal, parietal, and temporal regions as well as insulae. Lower WM densities were observed throughout the WM. Bariatric surgery and concomitant weight loss resulted in global increase in WM density. Grey matter increase was limited to occipital and inferior temporal regions. Metabolic variables were associated with brain densities. We conclude that weight loss results in global recovery of WM as well as local recovery of grey matter densities. These changes likely reflect improved brain tissue integrity. Hum Brain Mapp 37:3745–3756, 2016.