Background The reward-related regions have been considered a crucial component in the regulation of eating behavior. Furthermore, appetite-related regions associated with reward can influence eating behaviors through altered functional activity related to food in brain areas associated with emotion, memory, sensory processing, motor function, and cognitive control. Purpose To investigate the key nodes in obese females of reward-related regions and, based on key nodes, to evaluate the directionality of functional connectivity between key nodes and appetite-related regions. Study Type Prospective. Population Twenty-eight obese and 28 normal-weight female controls of similar age. Field Strength/Sequence 3.0 T MRI and echo planar imaging (EPI) sequence, 3D BRAVO sequence. Assessment The fMRI data preprocessing was based on the Data Processing & Analysis of Brain Imaging and Statistical Parametric Mapping 12. Degree centrality calculation was based on the GRETNA toolkit and granger causality analysis were based on the DynamicBC toolbox. Statistical Tests: Independent two-sample t-tests were used to assess the differences in demographic and clinical data between two groups. Two-sample t-tests were conducted to test the difference in degree centrality and effective connectivity of key nodes between two groups. Results Compared with normal-weight controls, obese females showed an increased degree centrality in the left ventral striatum/caudate (t = 2.96808, P < 0.05) and decreased degree centrality in right orbitofrontal cortex (OFC) (t = -3.3558, P < 0.05). The obese females showed directional effective connectivity between left ventral striatum/caudate and several regions (left inferior temporal gyrus, fusiform gyrus, postcentral gyrus, and right precentral gyrus) (P < 0.05). Directional effective connectivity was also observed between the right OFC and several regions (left middle temporal gyrus, cuneus, OFC, superior temporal gyrus, middle frontal gyrus, and right inferior parietal lobule) (P < 0.05). Data Conclusion The left ventral striatum/caudate and right OFC are key nodes in reward-related regions. The key nodes with reward processing mainly enhance visual processing of information and further participate in cognitive, attention, and sensorimotor processing. Technical Efficacy: Stage 4. J. Magn. Reson. Imaging 2019;50:541-551.