Research Article: Adenosine stimulates hepatic glycogenolysis via adrenal glands–liver crosstalk in mice

Date Published: December 21, 2018

Publisher: Public Library of Science

Author(s): Miki Tadaishi, Yutaro Toriba, Makoto Shimizu, Kazuo Kobayashi-Hattori, Jean-Marc A. Lobaccaro.


Adenosine signaling is involved in glucose metabolism in hepatocytes and myocytes in vitro. However, no information is available regarding the effect of adenosine on glucose metabolism in vivo. Thus, we examined how extracellular adenosine acts on glucose metabolism using mice. Subcutaneous injections of adenosine (10, 25, and 50 mg/kg bodyweight) dose-dependently increased blood glucose levels, with the peak occurring at 30 min post injection. At 30 min after adenosine injection (25 mg/kg bodyweight), glycogen content in the liver, but not the skeletal muscle, was significantly decreased. Hepatic glycogen depletion by fasting for 12 h suppressed the increase of blood glucose levels at 30 min after adenosine injection. These results suggest that adenosine increases blood glucose levels by stimulating hepatic glycogenolysis. To investigate the effect of adenosine on the adrenal gland, we studied the glycogenolysis signal in adrenalectomized (ADX) mice. Adenosine significantly increased the blood glucose levels in sham mice but not in the ADX mice. The decrease in hepatic glycogen content induced by adenosine in the sham mice was partially suppressed in the ADX mice. The level of plasma corticosterone, the main glucocorticoid in mice, was significantly increased in the sham mice by adenosine but its levels were low in ADX mice injected with either PBS or adenosine. These results suggest that adenosine promotes secretion of corticosterone from the adrenal glands, which causes hepatic glycogenolysis and subsequently the elevation of blood glucose levels. Our findings are useful for clarifying the physiological functions of adenosine in glucose metabolism in vivo.

Partial Text

Blood glucose, which is used as the energy source for the entire body, is constantly regulated. During fasting, the liver is the main organ that produces glucose via glycogenolysis and gluconeogenesis to maintain a normal level in the blood. When the glycogen pool in the liver is exhausted, energy metabolism shifts from glucose to lipid metabolism [1].

In this study, we examined the effect of adenosine on glucose metabolism in vivo. When adenosine was subcutaneously administered to mice, it increased blood glucose levels and the AUC in a dose-dependent manner (Fig 1), suggesting that adenosine enhances glucose production in vivo. To clarify the mechanism by which adenosine elevated blood glucose levels, we focused on glycogenolysis. Changes in the content of glycogen were measured 30 min after a subcutaneous injection of 25 mg/kg bw adenosine as this was the minimum dose at which a significant change in the blood glucose level was observed. The significant decrease in the glycogen content in the liver under this condition (Fig 2A) suggests that the enhanced glucose production induced by adenosine results from the degradation of hepatic glycogen. In contrast to the liver, no change in the skeletal muscle glycogen content was observed between the control and adenosine groups (Fig 2B). Although the activation of the A1 adenosine receptor is known to stimulate glucose uptake in skeletal muscle [9, 12], our study showed that adenosine affected neither glycogen breakdown nor synthesis in the muscle at 30 min after injection. To confirm whether the increase in blood glucose levels induced by adenosine depends on hepatic glycogen content, we examined it under fed or fasted conditions. In the fasted state where glycogen was depleted, adenosine had no effect on blood glucose levels and hepatic glycogen content (Fig 3). These results suggest that the increased blood glucose levels induced by adenosine result from the stimulation of hepatic glycogenolysis.