Vitamin B12 supplementation attenuates endoplasmic reticulum stress and neuronal cell death in the cerebral cortex of high-fat high-sucrose-fed male mice.

INTRODUCTION: Increased consumption of a high-calorie diet results in the development of metabolic disorders and associated neurological impairments, ultimately leading to cognitive decline. Metabolic disturbances such as hyperglycaemia, systemic insulin resistance, and hyperhomocysteinemia (HHcy) are linked to neurodegenerative diseases. These conditions share a common pathogenic feature of increased susceptibility to protein misfolding and aggregation, which triggers endoplasmic reticulum (ER) stress. Vitamin B12 is vital for brain health, and its deficiency is associated with HHcy and ER stress. This study investigated the effect of vitamin B12 supplementation on diet-induced metabolic disorder-associated ER stress and neurobehavioral outcomes in mice. METHODS: Two-month-old C57BL/6J male mice were randomly assigned to three groups and fed with respective diets for 8 months: Control (C) group (B12: 25 μg/kg diet), HFHS (high-fat, high-sucrose diet; B12: 25 μg/kg), and HFHS+B12 (B12: 50 μg/kg). RESULTS: Fasting blood glucose, glucose tolerance, triglycerides, and total cholesterol were similar across all groups. The HFHS diet led to body weight gain, higher insulin levels, elevated homocysteine (Hcy), and HOMA-IR compared to C group. However, B12 supplementation to HFHS mice significantly reduced Hcy levels compared to HFHS group. Additionally, the HFHS diet resulted in ER stress, neuronal apoptosis and astrogliosis in the cerebral cortex. However, B12 supplementation to HFHS group mitigated ER stress, protected against neuronal cell death, and reduced astrogliosis. Moreover, B12 supplementation enhanced neurotrophic support and reduced anxiety-like behaviour in HFHS+B12 group. CONCLUSIONS: Overall, these findings suggest that B12 supplementation confers protection against Hcy-induced ER stress and apoptosis, highlighting its potential as a neuroprotective agent.