Daily Rhythms in Metabolic Liver Enzymes and Plasma Glucose Require a Balance in the Autonomic Output to the Liver

Daily variations in plasma glucose concentrations are controlled by the biological clock, located in the suprachiasmatic nucleus. Our previous studies indicated an important role for the sympathetic innervation of the liver in the generation of the daily glucose rhythm. In the present study, we investigated further the role of the autonomic nervous system (ANS) in the genesis of the plasma glucose rhythm. First, we showed that complete removal of the autonomic inputs to the liver did not impair the plasma glucose rhythm or the daily expression of the glucoregulatory enzymes in the liver. Consequently, we studied whether the daily glucose rhythm is driven by the daily feeding activity in denervated animals. Surprisingly, complete denervation combined with a noncircadian feeding schedule also did not abolish the 24-h profile in plasma glucose or all daily rhythms in the gene expression of liver enzymes. These results demonstrate that the mechanisms used by the suprachiasmatic nucleus to control the rhythmic expression of glucose-metabolizing enzymes and the 24-h rhythm in plasma glucose concentrations are highly versatile and the glucose rhythm can be maintained in absence of hepatic ANS input and/or a day/night rhythm in feeding activity. Interestingly, a hepatic sympathectomy or parasympathectomy did abolish the plasma glucose rhythm, demonstrating that a unilateral denervation of the liver is more deleterious to maintaining the rhythmic liver metabolism than a complete removal of both branches. This observation supports the notion that an unbalanced ANS in obesity and diabetes accounts for the disturbed glucose balance in these disorders.