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 associatedwith 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.