Obesity-induced Nerve Degeneration and Inflammation: Therapeutic Effects of β-Hydroxybutyrate and Melatonin on Pyroptosis, ER Stress, and Hippocampal Dysfunction in High-Fat Diet-Fed Rats

Obesity-induced neurodegeneration is mediated by multiple pathological mechanisms, including inflammation, oxidative stress, pyroptosis, and endoplasmic reticulum (ER) stress, with pyroptosis and ER stress emerging as central contributors. This study investigated the neuroprotective efficacy of β-hydroxybutyrate (BHB) and melatonin, both individually and in combination, in mitigating these pathways and attenuating obesity-associated neurodegeneration. Thirty male Sprague-Dawley rats were allocated into five groups over a 7-week experimental period: (1) Control (standard diet); (2) High-fat diet (HFD), administered daily via oral gavage as an emulsion; (3) HFD + BHB (4% in drinking water); (4) HFD + melatonin (10 mg/kg/day in drinking water); and (5) HFD + BHB + melatonin. Post-treatment, blood and brain tissues were analyzed for biochemical markers, histopathological changes, and mRNA expression levels of pyroptosis-related (NLRP3, Caspase-1, Caspase-3, Caspase-11, GSDMD, NF-κB, IL-1β, IL-10) and ER stress-related (BIP, CHOP, sXBP1, TXNIP) genes via quantitative RT-PCR. Co-administration of BHB and melatonin significantly elevated serum ketone levels, ameliorated HFD-induced dyslipidemia, and attenuated weight gain (p < 0.001). Histopathological analysis revealed preserved neuronal density, volume, and architecture in the hippocampal CA1 and dentate gyrus (DG) regions, alongside reduced neurodegeneration (p < 0.001). The combined intervention suppressed neuroinflammatory markers and oxidative stress while elevating anti-inflammatory IL-10 levels. Furthermore, it downregulated pyroptosis-related (NLRP3, Caspase-1, Caspase-3, Caspase-11, GSDMD, NF-κB, IL-1β) and ER stress-related (BiP, CHOP, sXBP1, TXNIP) gene expressions (p < 0.001), suggesting a dual mechanism of action. BHB and melatonin demonstrate significant potential in counteracting obesity-driven neurodegeneration through synergistic anti-inflammatory, anti-pyroptotic, and ER stress-modulating effects. Their combined administration presents a multi-targeted therapeutic strategy to preserve neuronal integrity and mitigate brain damage in obesity. These findings corroborate prior evidence and underscore the translational relevance of BHB and melatonin in managing obesity-related neural pathologies.