Central dopamine is thought to play a significant role in obesity. In support of this idea, animal studies and one human positron emission tomography (PET) study have found reduced postsynaptic D2-like receptor availability in the striatum in obesity, with lower D2 receptor availability associated with higher weight. In addition, reward sensitivity, known to be related to dopamine function, has also been implicated in obesity and obesity-related eating behavior. These reports have led to the concept that dopaminergic abnormalities (e.g. reduced D2-like receptors) influence reward sensitivity, leading to altered eating behaviors and eventually obesity. However, there are several critical limitations that limit the strength of their conclusions and thus the interpretations and speculations embedded in literature that relies on this work. First, estimates of D2-like receptors in humans have been confounded by potential differences in endogenous dopamine release since the PET ligand (raclopride) used is known to be displaceable from receptors by endogenous dopamine. Second, failure to rigorously screen obese individuals for diabetes confounds conclusions, since diabetes has been independently associated with dopaminergic abnormalities. Finally, no human studies have addressed whether reduced D2-like receptor levels are a risk factor for obesity, a consequence of engaging in obesity related behaviors or being obese or all of the above. To clarify these issues, we propose to measure postsynaptic D2-like receptor binding with a PET ligand that, unlike raclopride, does not compete with endogenous dopamine and thus provides an unconfounded measure of D2-like receptors (NMB). Obese and lean subjects will be scanned and tested for behavioral features thought to be associated with dopamine and obesity (e.g. reward sensitivity) (Time 1). Obese subjects then will be assigned to a weight loss program that includes intensive monitoring and dietary and behavioral education. At the end of this year, all subjects will be scanned and tested again (Time 2). Results will determine if obesity status is associated with unconfounded measurements of reduced D2-like receptors in specific brain regions (e.g. ventral striatum and hypothalamus), whether individuals'D2-like receptor status is associated with dopamine-linked personality traits and with weight loss. This information is essential for accurately defining the role of the central dopamine system in obesity and for linking animal and human literature in this field.

Public Health Relevance

This project will address the neurobiological underpinnings of obesity. We will determine whether dopamine receptors in the brain are reduced in obesity and whether they are affected by weight loss. In addition, we will determine whether dopamine receptors are related to behaviors that are associated with obesity. This information will be useful in devising new interventions for obesity and understanding the full effect of obesity on the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK085575-03
Application #
8228170
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (O1))
Program Officer
Hunter, Christine
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$426,079
Indirect Cost
$145,764
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Hershey, Linda A; Perlmutter, Joel S (2014) Smoking and Parkinson disease: where there is smoke there may not be fire. Neurology 83:1392-3
Eisenstein, Sarah A; Antenor-Dorsey, Jo Ann V; Gredysa, Danuta M et al. (2013) A comparison of D2 receptor specific binding in obese and normal-weight individuals using PET with (N-[(11)C]methyl)benperidol. Synapse 67:748-56
Eisenstein, Sarah A; Koller, Jon M; Piccirillo, Marilyn et al. (2012) Characterization of extrastriatal D2 in vivo specific binding of [ýýýýýF](N-methyl)benperidol using PET. Synapse 66:770-80