Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction
Subhashis Banerjee, S. P. Ghoshal, Joseph R. Stevens, Kyle S. McCommis, Su Gao, Mauricio Castro‐Sepúlveda, María Luisa Mizgier, C. Giŗardet, K. Ganesh Kumar, José E. Galgani, Michael L. Niehoff, Susan A. Farr, Jinsong Zhang, Andrew A. Butler
Abstract
) expression, suggesting a link with gluconeogenesis. Our previous data suggest that adropin suppresses gluconeogenesis in hepatocytes. Liver-specific adropin knockout (LAdrKO) mice exhibit increased glucose excursions following pyruvate injections, indicating increased gluconeogenesis. Gluconeogenesis is also increased in primary cultured hepatocytes derived from LAdrKO mice. Analysis of circulating insulin levels and liver expression of fasting-responsive cAMP-dependent protein kinase A (PKA) signaling pathways also suggests enhanced responses in LAdrKO mice during a glucagon tolerance test (250 µg/kg intraperitoneally). Fasting-associated changes in PKA signaling are attenuated in transgenic mice constitutively expressing adropin and in fasting mice treated acutely with adropin peptide. In summary, hepatic adropin expression is regulated by nutrient- and clock-dependent extrahepatic signals. CR induces pronounced postprandial peaks in hepatic adropin expression. Rhythms of hepatic adropin expression appear to link energy balance and cellular stress to the intracellular signal transduction pathways that drive the liver fasting response.