Ginsenoside Rg5 attenuates hepatic glucagon response via suppression of succinate-associated HIF-1α induction in HFD-fed mice

Ginsenosides regulate glucose homeostasis. This study investigated the effect of ginsenoside Rg5 (Rg5) on the hepatic glucagon response, focusing on the regulation of metabolism. Mice fed a high-fat diet (HFD) showed increased hepatic glucose production (HGP). We observed the effects of Rg5 on hepatic fatty acid oxidation and glucagon response. The regulation of phosphodiesterase (PDE) 4B by succinate was also investigated in hepatocytes. Rg5 inhibited endogenous glucose production in HFD-fed mice. Rg5 reduced cyclic AMP (cAMP) accumulation and inhibited transcriptional regulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by dephosphorylation of the cAMP response element-binding transcription factor in the liver, demonstrating the inhibitory effect on hepatic glucagon response. HFD feeding increased succinate accumulation in the liver due to the reversal of succinate dehydrogenase activation and triggered hypoxia-inducible factor-1 alpha (HIF-1 alpha) induction. Succinate prevented cAMP degradation by inactivating PDE4B, thereby increasing cAMP accumulation in response to glucagon. Knockdown of HIF-1 alpha with small interfering RNA diminished the effect of succinate, indicating that HIF-1 alpha was essential for succinate to inactivate PDE4B. Rg5 inhibited succinate accumulation in hepatocytes by combating fatty acid oxidation, and thus reduced cAMP accumulation by blocking succinate/HIF-1 alpha induction. Rg5 reduced HGP as a consequence of the inhibition of the glucagon response. Succinate acted as a metabolic signal to enhance the hepatic glucagon response. Rg5 reduced hepatic succinate accumulation by combating fatty acid oxidation and attenuated the hepatic glucagon response by suppressing succinate/HIF-1 alpha induction, suggesting that succinate-associated HIF-1 alpha induction in hepatocytes might be a therapeutic target in the treatment of diabetes.