Metabolome Atlas of Brain Reveals Regional Shared and Unique Metabolic Drifts in Response to Type 2 Diabetes in Male Mice

ABSTRACT Type 2 diabetes (T2D), with continuously increasing incidence worldwide, impairs not only peripheral organs but also the central nervous system. However, the brain‐region‐specific metabolic signature of T2D remains unknown, which is crucial for understanding T2D neurological complications' mechanism and developing intervention. In this study, we constructed a metabolome atlas of T2D and control brain in male mice from 7 anatomical regions using liquid chromatography‐mass spectrometry‐based metabolomic and lipidomic techniques. In total, 673 metabolites were identified, including energy substrates, amino acids, neurotransmitters, phospholipids, and signaling lipids. We found that the mouse brain displayed region‐specific metabolic architecture; however, functionally connected regions (cerebrum, spinal cord, brainstem and cerebellum) exhibited metabolic similarity. Most metabolites exhibited significant differences between brain regions in T2D versus control mice, and no significantly differential metabolites were shared across all brain tissues. Metabolome of hypothalamus and olfactory bulb were the most affected by T2D. A common shift in lipid patterns was observed across brain regions in T2D mouse, like increased triacylglycerols while reduced fatty acids and diacylglycerols. This study offers the first evidence that T2D drives a marked rise in the neurotoxic lipid class of primary amides while simultaneously depleting the neuroprotective N‐acylethanolamines. We observed a dramatic decrease in sphingolipids in the hippocampus under T2D, likely due to T2D‐induced neurotoxicity that damages the myelin sheath, causing sphingolipid depletion and accelerating decomposition. Alterations in amino acid profiles were also detected. These results uncover the molecular mechanism of T2D‐induced brain alterations and deliver an open‐access, region‐resolved metabolomic reference for future research.