Excessive visceral fat is associated with greater metabolic fluctuation and increased risk for dementia in older adults (1). However, the mechanisms behind this relationship are poorly understood. As increased adiposity is also related to lower levels of circulating C-Reactive Protein (CRP), a marker for inflammation (2), we hypothesized that changes in brain structure that occur in individuals with high central adiposity would be driven by higher levels of circulating CRP.Fasting blood samples and high-resolution Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) images were obtained from 103 participants aged 40-60 years (mean = 49.63, S.D = 6.47) on a 3T Siemens Skyra scanner. These images were then processed through Freesurfer Image Analysis Suite, which is documented and freely available for download online. Image processing involved first motion correction and averaging of two volumetric weighted images, computerized removal of non brain tissue using a hybrid watershed/surface deformation procedure, automated Talairach transformation, intensity normalization, tessellation of the gray matter, white matter boundary, automated topology correction and surface deformation following intensity gradients to optimally place the gray/white and gray/cerebrospinal fluid borders at the location where the greatest shift in intensity defines the transition to the other tissue class. Visceral fat was measured using dual energy X-Ray absorptiometry (DXA). CRP levels were assessed with an enzyme linked immunosorbent assay (ELISA). Statistical analysis of the data was carried out in two parts. First, statistical comparisons of global data and surface maps were generated by computing a generalized linear model (GLM) of the effects of visceral fat mass and volume on thickness at each vertex in the cortical mantle using the Query Design Estimate Contrast (QDEC) interface of Freesurfer. QDEC is a single binary application included in the Freesurfer distribution that is used to perform group averaging and inference on cortical morphometric data produced by the Freesurfer processing streamMaps were created using statistical thresholds of .05 and were smoothed to a full width half maximum (FWHM) of 20 mm. Since the QDEC analyses involved performing a GLM analysis at 160,000 vertices, maps were corrected for multiple comparisons by means of a cluster wise procedure using the Monte Carlo Null-Z simulation method adapted for cortical surface analysis and incorporated into the QDEC processing stream. For these analyses, a total of 10,000 iterations of simulation were performed for each comparison, each using a threshold of p < 0.05. Regions that were significantly related to high visceral fat were extracted and used as outcomes for subsequent mediation analysis. Statistical mediation was assessed using traditional causal steps.Individuals with higher visceral fat mass and volume had significantly thicker cortex in the right posterior cingulate gyrus (b = 0.29, p = 0.019, b = 0.31, p = 0.011, respectively), controlling for age, systolic blood pressure, total cholesterol level and blood glucose level. However, thickness in this region was not significantly related to elevations in CRP (b = 0.02, p = 0.076). As such, statistical mediation could not be establishedVisceral fat was significantly associated with thicker cortex in the posterior cingulate gyrus. However, thicker cortex in the posterior cingulated gyrus was not significantly associated with circulating levels of CRP, our hypothesized mediator. It is possible that other circulating biomarkers (such as Brain Derived Neurotrophic Factor or insulin sensitivity) might have play a more prominent role in modulating the relationship between visceral fat and brain structure in middle age. The unintuitive direction of the relationship between visceral fat and thickness in this study is also noteworthy; high visceral fat was associated with thicker cortex in the posterior cingulated gyrus. We hypothesize that this occurred due to neuronal hypertrophy (3) or astrogliosis (4).While future studies are necessary, these results indicate central adiposity is associated with significant metabolic changes that impinge upon the central nervous system in middle age.