Impact of voluntary exercise on obesity-induced brain pathology: Insights from a multimodal approach in male Ldlr-/-.Leiden mice

Background: Impact of exercise on obesity-related brain pathology remains unclear. MRI is used to detect obesity-related brain changes, but its interpretation remains unclear. We aimed to evaluate effects of voluntary exercise on obesity-induced brain pathology and determine whether MRI signal intensity and diffusion metrics capture these alterations. Methods: Male Ldlr-/-.Leiden mice were fed a low-fat chow diet from 2 to 4 months of age. At 4 months, mice (n = 10) were sacrificed as baseline group representing young non-obese adult mouse brains. Remaining mice were fed a high-fat diet (HFD) for another 6 months with (HFD + exercise) or without (HFD) access to running wheels (n = 16/group each). MRI (T1-weighted, T2-weighted, T2*-weighted, and diffusion metrics) was analyzed for signal intensity and microstructural changes, rather than visible cerebral small vessel disease lesions. Immunohistochemistry (IHC), polarized light imaging (PLI), and qPCR were used to investigate microvasculature, astro-/microgliosis, and axonal/myelin integrity. We studied MRI's underlying pathology by its co-registration with IHC and PLI. Results: HFD induced microvascular remodeling, astro-/microgliosis, and axonal injury, while myelin integrity remained unaffected. Exercise did not fully reverse these changes but was associated with milder microgliosis, microvascular remodeling and axonal alterations. MRI revealed reduced T2-weighted signal intensity in white matter (WM) (HFD), and in both WM and grey matter (GM) (HFD + exercise). Additionally, GM microglial density correlated negatively with diffusion metrics in the HFD + exercise group. Conclusion: Voluntary exercise offered partial mitigation of HFD-induced damage, with indications of less severe microgliosis, microvascular remodeling and axonal disruption. Pathology-MRI co-registration revealed associations between neuroinflammation and diffusion metrics, supporting multimodal approaches to interpret MRI and guide development of optimal targeted interventions for obesity-related brain pathology.