Papel do nervo vago na regulação fisiológica e circadiana hepática

Abstract

Introduction: The biological clock adapts the body's physiology to daily 24-hour cycles, anticipating and coordinating physiological responses according to environmental cues. Light is classically referred to as the main clue in the synchronization of circadian rhythms, but recent studies indicate that feeding/feeding schedule is also an important regulator of peripheral clocks and the oscillation of physiological functions throughout the day. The liver has an internal clock that adjusts physiological processes to its relevant time of day, and misalignment of its rhythmic functions can lead to liver complications. However, the components and circuitry involved in synchronizing your peripheral clock through food are not well understood. Hypothesis: As the vagus nerve is an important source of sensory and motor innervation to the liver, and also reaches the master clock in the central nervous system, we hypothesized that this neural circuit could be involved in biological clock synchronization and rhythmic physiological functions in the liver. Methods: To test our hypothesis, we performed lateral cervical vagotomy (VNX) in animals maintained under a normal light cycle and fed an ad libitum diet. We performed gene expression assays (RT-PCR) for clock genes, global proteome analysis and physiological validation of liver functions, under standard and carbohydrate/lipid-rich diet conditions, at different times of the day. Results: VNX altered the mRNA levels of the Bmal1, Clock, Ror-α and Rev-Erbα clock genes in ZT6. On the other hand, VNX did not impact the daily cycles of corporal temperature and locomotor activity – classic outputs from the central biological clock. VNX altered the rhythmicity of serum glucose and hepatic glycogen stores under normal diet conditions. These changes were not accompanied by changes in food activity, intestinal motility and nutrient absorption. Different functional pathways in the liver were altered by VNX, as revealed by proteomics in ZT6. The metabolic impact was shown to be prominent, with an increase in glycolysis and fatty acid biosynthesis (initiation and elongation steps) in parallel with the reduction of beta-oxidation in the VNX group. To validate the biological relevance of these findings, we followed VNX mice for 5 weeks after surgery. VNX animals accumulated lipids in the liver, even when fed a standard diet. When we introduced diets rich in refined carbohydrates (HC) and rich in fatty acid (HFD), we noticed that the accumulation of liver fat in VNX animals became even more pronounced. Conclusion: Together, our results point to a relevant parasympathetic autonomic role on the regulation of the hepatic peripheral clock, possibly independent of the central clock and the modulation of nutrient absorption, being involved in the control of liver metabolism during the day. Furthermore, the reduction in cholinergic tone associated with hepatic chronodisruption predisposes to steatosis, and this accumulation is exacerbated in the presence of metabolic stress.