Short-term plasticity of gray matter associated with leptin deficiency and replacement

Abstract

Context: Leptin affects neurogenesis, neuronal growth, and viability. We previously reported that leptin supplementation increased gray matter (GM) concentration in the anterior cingulate gyrus (ACG), cerebellum, and inferior parietal lobule, areas that are also involved in food intake.

Objective: The aim of this study was to report the changes in brain structure at different states of leptin supplementation.

Design: We conducted a nonrandomized trial.

Setting and patients: We studied three adults with congenital leptin deficiency due to a mutation in the leptin gene.

Intervention: Patients received treatment with recombinant methionyl human leptin, with annual 11- to 36-d periods of treatment withholding followed by treatment restoration over 3 yr.

Main outcome measures: GM concentration (by voxel-based morphometry analysis of magnetic resonance scans) was correlated with body mass index (BMI) and leptin supplementation.

Results: Annually withholding leptin supplementation for several weeks increased BMI and reversed the original effects of leptin in the cerebellum and ACG. The changes in the ACG were consistent with an indirect effect of leptin mediated through increased BMI. In the cerebellum, where leptin receptors are most dense, GM changes appeared to be direct effects of leptin. Leptin restoration did not lead to recovery of GM in the short term but did lead to an unexpected GM increase in the posterior half of the left thalamus, particularly the pulvinar nucleus.

Conclusion: These findings provide the first in vivo evidence of remarkably plastic, reversible, and regionally specific effects of leptin on human brain morphology. They suggest that leptin may have therapeutic value in modulating plasticity-dependent brain functions.

Fig. 1.

Statistical parametric maps indicate effects of leptin supplementation and withholding of supplementation on brain structure. Areas where 18 months of leptin supplementation previously increased GM concentration are shown at left, superimposed on the “glass-brain” [Adapted with permission from J. A. Matochik et al.: J Clin Endocrinol Metab 90:2851–2854, 2005 (13). © The Endocrine Society.] Colored voxels in the right panel depict decreases in GM concentration (P < 0.005 uncorrected) after withholding leptin for 11–36 d (mean, 28.6) in the current study, superimposed on sagittal slices 13 and 10 mm to the left of midline on a normalized T1 image. AC, Anterior cingulate; CB, cerebellum; IPL, inferior parietal lobule.

Fig. 2.

Graphs quantify GM change for all subjects and scans at the a priori hypothesized location in the cerebellum (−10, −46, −46) and near the a priori hypothesized location within the anterior cingulate (−12, 42, 14). +, More than 10 months of daily leptin; −, 11–36 d without leptin (mean, 28.6); brief, 11–22 d after daily leptin was restored (mean, 16.1).

Fig. 3.

Statistical parametric maps indicate areas where GM concentration showed positive covariation with days of leptin supplementation (blue voxels) and negative covariation with BMI (yellow voxels). Results (uncorrected voxel, P < 0.005; and whole-brain corrected spatial extent, P < 0.05) are superimposed on a normalized T1 image for sagittal slices 29 mm to the left (upper left panel) and 34 mm to the right of midline (upper right panel), and axial slices 3 mm below (lower left panel) and 29 mm above the anterior commissure (lower right panel). AC, Anterior cingulate; CB, cerebellum; mfg, middle frontal gyrus; stg, superior temporal gyrus; itg, inferior temporal gyrus; hip, hippocampus; IPL, inferior parietal lobule.