Network-Level Convergence of Adiposity-Related Gray Matter Alterations: A Coordinate-Based Connectome Mapping...

Obesity is commonly associated with atrophy-like gray matter changes, such as lower gray matter volume or density, yet the affected regions reported vary widely across studies. It remains unclear whether these heterogeneous loci converge on a reproducible large-scale network, and whether weight-loss-related increases in gray matter map onto the same network or a distinct set of functional systems. We identified loci of adiposity-related gray matter reduction and post-weight-loss increases from 38 published whole-brain voxel-based morphometry studies, including case-control, dimensional adiposity, and longitudinal weight-loss contrasts. Using coordinate-based connectome mapping applied to a large normative resting-state functional connectome, we reconstructed networks associated with adiposity-related structural alterations. We further performed imaging transcriptomic and gene set enrichment analyses to characterize the molecular programs associated with the adiposity-related network. Gray matter reductions associated with adiposity converged on a reproducible, distributed large-scale network primarily involving frontoparietal control, cingulo-opercular, default mode, and Visual1 systems. In contrast, GMV/GMD increases following weight loss showed a distinct system-level distribution, with the largest contributions in cingulo-opercular, somatomotor, and dorsal attention systems, and comparatively limited representation in default mode and frontoparietal control networks. Imaging transcriptomic analyses further linked the adiposity-related network to coordinated gene expression patterns, and gene set enrichment analyses highlighted pathways related to mitochondrial energy metabolism, synaptic signaling, ion transport, and cellular protein homeostasis. Adiposity-related gray matter alterations converge on a reproducible large-scale network, but the system-level pattern differs across categorical obesity, dimensional adiposity, and GMV/GMD increases following weight loss. Weight-loss-related gray matter increases are not a simple mirror reversal of the cross-sectional network, and imaging transcriptomic analyses implicate coordinated molecular programs related to mitochondrial energetics, synaptic signaling, ion transport, and protein homeostasis.