Melatonin Ameliorates High Fat Diet Induced Oxidative Stress-Mediated Insulin Resistance, Amyloid Burden and Memory Dysfunction in Female Mice and their offspring

Abstract High fat diet (HFD) is a prime factor, which contributes to the present epidemic of metabolic syndrome. HFD induces oxidative stress (OS) that in turn causes neuroinflammation, neurodegeneration, synaptic dysfunction, insulin resistance and amyloid burden. Pineal gland secretes a potent anti-apoptotic hormone, melatonin that has the potential to nullify the toxic effect of reactive oxygen species (ROS) and ameliorate various complications induced by HFD in rodent models. We aimed to find the therapeutic effects of melatonin against HFD-induced neuroinflammation and neurodegeneration mediated by OS in pregnant mice and their offspring. The neuroprotective effects of melatonin against HFD induced neurotoxicity were analyzed by Western blotting and immunofluorescence in the brain homogenates of pregnant albino mice and their offspring. Short and long term memory loss was evaluated. HFD significantly induced OS leading to neuroinflammation and apoptotic neurodegeneration in cortex and hippocampus of the pregnant mice and their offspring. However, administration of melatonin with HFD significantly improved synaptic dysfunction and inhibited both the neuroinflammation and neurodegeneration in albino mice. Here, we report that melatonin exerts these effects via SIRT1 mediated NRF-2/HO-1 signaling pathway to reduce HFD-induced OS and insulin resistance. This study revealed that melatonin could reverse HFD induced multiple complications leading to the memory dysfunction in pregnant female mice and their successive generation via activation of SIRT1/NRF2 signaling pathway.