Obesity-induced oxidative stress and cGMP depletion suppress cerebellar α2,3-Na+,K+-ATPase activity in female mice.

Abstract

Obesity is a major metabolic disorder linked to neuroinflammation and cognitive decline. Beyond hypothalamic alterations, emerging evidence indicates that extra-hypothalamic regions, including the cerebellum, are vulnerable to obesity-induced neurotoxicity. This study investigated whether high-fat diet (HFD)-induced obesity causes cerebellar oxidative stress, impairs Na⁺,K⁺-ATPase (NKA) activity, and triggers molecular features resembling brain aging in female Balb/C mice. Chronic 10-week HFD intake established a marked obese phenotype, characterized by increased adiposity, fasting hyperglycemia, hyperlipidemia, and elevated serum TNF-α. In the cerebellum, obesity induced a selective, expression-independent reduction in α2,3-NKA isoform activity, accompanied by a marked depletion of tissue cGMP levels. This functional impairment was driven by an oxidative microenvironment, evidenced by elevated H₂O₂ and TBARS levels and increased 4-HNE accumulation. Concomitantly, obese animals mounted an adaptive antioxidant response characterized by increased GST, GR, and GPx activities, reduced glutathione (GSH) consumption, and ERK1/2-mediated nuclear translocation of Nrf2, alongside structural membrane lipid remodeling (elevated cholesterol and reduced phospholipids). In summary, chronic obesity induces robust lipoxidative stress and suppresses cerebellar cGMP signaling and α2,3-NKA activity in female mice, recapitulating key molecular hallmarks of natural brain aging.