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      Relationship of Dopamine Type 2 Receptor Binding Potential With Fasting Neuroendocrine Hormones and Insulin Sensitivity in Human Obesity

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          Abstract

          OBJECTIVE

          Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity.

          RESEARCH DESIGN AND METHODS

          We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S I) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [ 18F]fallypride (radioligand that competes with endogenous DA) in lean ( n = 8) and obese ( n = 14) females. Fasting hormones were collected prior to scanning and S I was determined by modified oral glucose tolerance test.

          RESULTS

          Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S I was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand.

          CONCLUSIONS

          Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.

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          Most cited references 34

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          Reward, dopamine and the control of food intake: implications for obesity.

          The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated that this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control. Published by Elsevier Ltd.
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            Changes in brain activity related to eating chocolate: from pleasure to aversion.

             D M Small (2001)
            We performed successive H(2)(15)O-PET scans on volunteers as they ate chocolate to beyond satiety. Thus, the sensory stimulus and act (eating) were held constant while the reward value of the chocolate and motivation of the subject to eat were manipulated by feeding. Non-specific effects of satiety (such as feelings of fullness and autonomic changes) were also present and probably contributed to the modulation of brain activity. After eating each piece of chocolate, subjects gave ratings of how pleasant/unpleasant the chocolate was and of how much they did or did not want another piece of chocolate. Regional cerebral blood flow was then regressed against subjects' ratings. Different groups of structures were recruited selectively depending on whether subjects were eating chocolate when they were highly motivated to eat and rated the chocolate as very pleasant [subcallosal region, caudomedial orbitofrontal cortex (OFC), insula/operculum, striatum and midbrain] or whether they ate chocolate despite being satiated (parahippocampal gyrus, caudolateral OFC and prefrontal regions). As predicted, modulation was observed in cortical chemosensory areas, including the insula and caudomedial and caudolateral OFC, suggesting that the reward value of food is represented here. Of particular interest, the medial and lateral caudal OFC showed opposite patterns of activity. This pattern of activity indicates that there may be a functional segregation of the neural representation of reward and punishment within this region. The only brain region that was active during both positive and negative compared with neutral conditions was the posterior cingulate cortex. Therefore, these results support the hypothesis that there are two separate motivational systems: one orchestrating approach and another avoidance behaviours.
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              Relation of reward from food intake and anticipated food intake to obesity: a functional magnetic resonance imaging study.

              The authors tested the hypothesis that obese individuals experience greater reward from food consumption (consummatory food reward) and anticipated consumption (anticipatory food reward) than lean individuals using functional magnetic resonance imaging (fMRI) with 33 adolescent girls (mean age = 15.7, SD = 0.9). Obese relative to lean adolescent girls showed greater activation bilaterally in the gustatory cortex (anterior and mid insula, frontal operculum) and in somatosensory regions (parietal operculum and Rolandic operculum) in response to anticipated intake of chocolate milkshake (vs. a tasteless solution) and to actual consumption of milkshake (vs. a tasteless solution); these brain regions encode the sensory and hedonic aspects of food. However, obese relative to lean adolescent girls also showed decreased activation in the caudate nucleus in response to consumption of milkshake versus a tasteless solution, potentially because they have reduced dopamine receptor availability. Results suggest that individuals who show greater activation in the gustatory cortex and somatosensory regions in response to anticipation and consumption of food, but who show weaker activation in the striatum during food intake, may be at risk for overeating and consequent weight gain. (PsycINFO Database Record (c) 2008 APA, all rights reserved).
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                May 2012
                11 April 2012
                : 35
                : 5
                : 1105-1111
                Affiliations
                1Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
                2Department of Radiology, Vanderbilt University School of Medicine, Nashville, Tennessee
                3Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
                4Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
                5National Institute of Drug Abuse, Bethesda, Maryland
                6Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
                Author notes
                Corresponding author: Julia P. Dunn, julia.dunn@ 123456va.gov .
                Article
                2250
                10.2337/dc11-2250
                3329842
                22432117
                © 2012 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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                Categories
                Original Research
                Pathophysiology/Complications

                Endocrinology & Diabetes

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