Leptin replacement alters brain response to food cues in genetically leptin-deficient adults

Abstract

A missense mutation in the ob gene causes leptin deficiency and morbid obesity. Leptin replacement to three adults with this mutation normalized body weight and eating behavior. Because the neural circuits mediating these changes were unknown, we paired functional magnetic resonance imaging (fMRI) with presentation of food cues to these subjects. During viewing of food-related stimuli, leptin replacement reduced brain activation in regions linked to hunger (insula, parietal and temporal cortex) while enhancing activation in regions linked to inhibition and satiety (prefrontal cortex). Leptin appears to modulate feeding behavior through these circuits, suggesting therapeutic targets for human obesity.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Greater activation in parietal cortex and insula in the absence of leptin supplementation. Images are SPM T maps of significant BOLD signal change greater when leptin supplementation was discontinued (vs. during supplementation) for the contrast high-calorie > low-calorie stimuli. Left image (z = 29) shows a significant cluster in the region of the left parietal supramarginal gyrus: extent = 52 voxels, t = 4.06, z score = 4.05, peak voxel x y z coordinates are −64 −48 26. Right image (z = 0) shows significant clusters bilaterally in the insula. Left insula: extent = 20 voxels, t = 3.9, z score = 3.89, peak voxel at −36 10 2. Right insula: extent = 26 voxels, t = 3.45, z score = 3.45, peak voxel at 48 0 0. Images are in neurologic orientation, displayed on the SPM5 EPI template. Coordinates are in MNI space, contrast comparisons at P < 0.001 uncorrected.

Fig. 2.

Leptin supplementation enhanced activation in PFC and cerebellum. Images are SPM T maps of significantly greater BOLD response during leptin supplementation (vs. 33 days after discontinuation) for the contrast of high-calorie > low-calorie stimuli. Left image (x = 0) shows largest significant clusters in the medial frontal gyrus (MFG): left MFG extent = 102, t = 4.70, z score = 4.70, peak voxel at −2 32 −12; right MFG extent = 202, t = 4.69, z score = 4.58, peak voxel at 10 56 12. Right image (x = 14) shows the largest significant cluster in the right cerebellum: extent = 379, t = 5.39, z score = 5.38, peak voxel at 16 −84 −24. Images are in neurologic orientation, displayed on the SPM5 EPI template. Coordinates are in MNI space, contrast comparisons at P < 0.001 uncorrected.

Fig. 3.

Region of interest analysis by subject by fMRI scan for the contrast high-calorie > low-calorie stimuli. Each subject showed greater activation in the insula but less activation in the right cerebellum and prefrontal cortex (medial frontal gyrus, MFG) when no leptin supplementation (center), compared with test sessions when supplemental leptin was administered (left and right).