Glucose metabolism drives the hierarchical propagation of gray matter atrophy from the orbitofrontal cortex in obesity.

To characterize the directional influence among brain regions across a metabolic gradient in obesity, thereby offering insights into the neurobiological pathways linking obesity to Type 2 Diabetes Mellitus (T2DM). The study included 85 individuals with obesity and 89 healthy controls (HCs). All participants underwent structural MRI, glycemic status (normoglycemia (NGM), prediabetes, or T2DM) and other metabolic risk factors were assessed. A causal structural covariance network was constructed to investigate the directional relationships of gray matter (GM) alterations in obesity across distinct glucose metabolic states. This was achieved by applying Granger Causality Analysis (GCA) to morphometric T1-weighted MRI data that were ordered across subjects according to glycated hemoglobin (HbA1c) levels. Relative to HCs, the obesity with NGM displayed restricted GM atrophy localized mainly within the orbitofrontal cortex (OFC), whereas those with prediabetes or T2DM exhibited widespread GM volume reductions involving the putamen, insula, thalamus, and multiple parietal and temporal regions, as well as a broader OFC area. The results of CaSCN analysis revealed that the OFC may serve as a core region in which atrophy is anchored, exerting a positive directional influence on the frontal, parietal, temporal, and occipital regions as HbA1c levels increase. Our findings identify a stepwise pattern of GM atrophy in obesity, characterized by a putative hierarchical organization anchored in the OFC that appears more pronounced with worsening glucose metabolism. These results underscore the OFC as a critical nodal hub that may serve as a potential target for early neuroprotective intervention.