<em>Portulaca oleracea</em> Extract Modulates Diet-Dependent Neuroplasticity in a Murine Model of NAFLD and Depression

Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a systemic condition with neuropsychiatric comorbidities, including depression. Growing evidence for the neuroprotective, antidepressant, and anxiolytic potential of Portulaca oleracea (PO) extract, provides a compelling rationale for investigating its effects in the interaction between dietary models of NAFLD and vulnerability to stress-related disorders. Fifty-four male (n = 27) and female (n = 27), 14- to 18-week-old C57BL/6N mice were fed either a methionine- and choline-deficient diet (MCD) or a methionine- and choline-controlled diet (MC) and half of the total were subjected to added chronic unpredictable mild stress (CUMS) and PO. MCD caused significant weight loss, whereas MC promoted weight gain. Conductually, MCD induced anhedonia- and anxiety-like behaviors, worsened by CUMS. MC diet reduced CUMS-induced anhedonia, though anxiety-like behavior emerged only under stress. Recognition memory was impaired in stressed MCD-fed mice, while MC-fed mice showed enhanced novel object preference. At cellular level, MCD suppressed hippocampal microglia and caused cortical astrocyte dysfunction, whereas MC diet promoted cortical neurogenesis potentiated through PO, abolished by chronic stress. These findings underscore the impact of dietary composition on PO’s systemic effects under chronic stress and support a mechanistic link between NAFLD-related dysfunction and depression-like phenotypes.