Noninvasive 40-Hz Light Flicker Rescues Circadian Behavior and Abnormal Lipid Metabolism Induced by Acute Ethanol Exposure via Improving SIRT1 and the Circadian Clock in the Liver-Brain Axis

Abstract

Sirtuin 1 (SIRT1) is a protein deacetylase with important cellular functions, as it regulates numerous processes, including the circadian rhythm in peripheral tissues. Efforts are ongoing to reveal how Sirt1 can be used to treat diseases, such as alcoholic liver disease (ALD), Alzheimer's disease, and liver fibrosis. We have recently shown that noninvasive exposure to 40-Hz light flicker activates hypothalamic SIRT1 gene expression, thereby regulating the central circadian clock. This study investigated the effects of 40-Hz light flicker in a mouse model of ALD. RNA sequencing (RNA-seq) analysis was performed to explore the potential pathways affected by 40-Hz light flicker. We found that 40-Hz light flicker significantly decreased the acute ethanol-induced increases in serum alanine aminotransferase (ALT) and serum triglyceride (TG) levels and reduced fat-droplet accumulation in mouse livers. Additionally, 40-Hz light flicker significantly suppressed ethanol-induced increases in sterol regulatory element binding protein 1 (SREBP-1) and fatty acid synthase (Fasn) levels. Furthermore, the ethanol induced significant decreases in both Sirt1 levels and phosphorylation of adenosine monophosphate-activated protein kinase subunit (AMPKa), compared with those in the control group. Strikingly, pretreatment with 40-Hz light flicker ameliorated such ethanol-induced decreases in SIRT1 levels and AMPKa phosphorylation. In addition, ethanol-induced increases in levels of brain and muscle arnt-like protein-1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), and period 2 (PER2) were reversed by 40-Hz light flicker. RNA-seq analysis revealed significant differences in expression of genes related to the AMPK signalling. Moreover, ethanol consumption altered mRNA levels of Sirt1 and circadian genes in the suprachiasmatic nucleus (SCN), indicating that ethanol influenced central pacemaker

Circadian Rhythms of the Hypothalamus: From Function to Physiology

“…A very interesting behavioral pattern in AD patients is the manifestation of Sundown Syndrome or “sundowing.” AD patients with sundowning express temporally-dependent behaviors of agitation, aggression, and/or confusion in the afternoon and evening hours [ 305 ]. Interestingly, a higher rate of sundowning is reported during the winter months when sunlight exposure is often limited [ 306 ]. Melatonin treatment for individuals with sundowning appears to reduce agitated behaviors [ 307 ].…”

40-Hz Blue Light Changes Hippocampal Activation and Functional Connectivity Underlying Recognition Memory

“…Relevant clinical research has been mostly limited to animal experiments. Animal studies have indicated that flashing blue light with a frequency of 40 Hz can significantly improve circadian rhythm disorders in mice with Alzheimer’s disease (APP/PS1), which further verifies the effect of light regulation on frequency characteristics ( Yao et al, 2020 ). In addition, neurological disease appears deficient in the gamma band of neural oscillation, and such deficits can be compensated by exposure to external sensory stimulation ( Uhlhaas and Singer, 2006 ; McDermott et al, 2018 ).…”

Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway

“…Paraiso et al found that the improvement of peripheral and central metabolic impairments was linked to a decrease in ceramides in both the liver and hippocampus through the liver-brain axis [61]. Yao et al showed that an abnormal lipid metabolism in the liver may cause disruptions in circadian behaviors though the liver-brain axis [62]. de Sousa Rodrigues et al showed that a high fat, high fructose diet and stress could affect liver and gut functioning, which can ultimately influence behavior through inflammatory mechanisms [63].…”