Effects of leptin deficiency and replacement on cerebellar response to food-related cues

Abstract

Leptin affects eating behavior partly by altering the response of the brain to food-related stimuli. The effects of leptin on brain structure have been observed in the cerebellum, where leptin receptors are most densely expressed, but the function of leptin in the cerebellum remains unclear. We performed a nonrandomized, prospective interventional study of three adults with genetically mediated leptin deficiency. FMRI was recorded three times each year during years 5 and 6 of leptin replacement treatment. Session 1 of each year occurred after 10 months of continuous daily replacement, session 2 after 33-37 days without leptin, and session 3 at 14-23 days after daily replacement was restored. Statistical parametric mapping software (SPM5) was employed to contrast the fMRI blood oxygenation level-dependent response to images of high-calorie foods versus images of brick walls. Covariate analyses quantified the effects of the duration of leptin replacement and concomitant changes in body mass on the cerebral responses. Longer duration of replacement was associated with more activation by food images in a ventral portion of the posterior lobe of the cerebellum, while simultaneous decreases in body mass were associated with decreased activation in a more dorsal portion of the same lobe. These findings indicate that leptin replacement reversibly alters neural function within the posterior cerebellum and modulates plasticity-dependent brain physiology in response to food cues. The results suggest an underexplored role for the posterior cerebellum in the regulation of leptin-mediated processes related to food intake.

Figure 1

Statistical parametric maps quantify areas across subjects and conditions where the blood oxygen-level dependant (BOLD) signal elicited by high-calorie food pictures was higher than that elicited by pictures of brick walls. Colored areas represent voxel t-scores > 3.85 (p < 0.001 uncorrected). For illustrative purposes, results are superimposed on a representative but not study-specific T1 image in MNI space for transaxial slices 18 mm below the level of the anterior commissure (AC), at the level of AC, and 8 mm above the AC. CB cerebellum, MB midbrain, Amy amygdala, OCC occipital cortex, Hip hippocampus, Str striatum, INS insula, Thal thalamus, IFG inferior frontal gyrus.

Figure 2

Statistical parametric maps quantify direct relationships of the duration of leptin replacement and Body Mass Index (BMI) to the blood oxygen-level dependant (BOLD) signal elicited by high-calorie food pictures, relative to brick walls. Left column: Areas where BOLD signal covaried with BMI. Middle column: Areas where BOLD signal covaried with duration of leptin replacement. Colored areas (neurological orientation) represent voxel t-scores > 3.01 (p < 0.005 uncorrected). Results are superimposed on a representative but not study-specific T1 image for sagittal slices 29 mm to the left of midline (top row), and coronal slices 50 mm (middle row) and 70 mm (bottom row) posterior to the anterior commissure. Right column: Green lines demarcate and white text labels the fissures and lobules of the cerebellum [60]. On the sagittal image, blue scale depicts areas where grey matter structure directly covaried with duration of leptin replacement in these same patients during 2005, 2006 and 2007, reprinted with permission [8].