Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction.

2020 
The micropeptide adropin encoded by the clock-controlled Energy homeostasis-associated gene is implicated in the regulation of glucose metabolism. However, its links to rhythms of nutrient intake, energy balance and metabolic control remains poorly defined. Using surveys of Gene Expression Omnibus datasets, we confirm that fasting suppresses liver adropin expression in lean C57L/6J (B6) mice. However, circadian rhythm data are inconsistent. In lean mice, CR induces bouts of compulsive binge feeding separated by prolonged fasting intervals, increasing NAD-dependent deacetylase sirtuin-1 signaling important for glucose and lipid metabolism regulation. CR upregulates adropin expression and induces rhythms correlating with cellular stress-response pathways. Furthermore, adropin expression correlates positively wth phosphoenolpyruvate carboxokinase-1 (Pck1) 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 PKA signaling pathways also suggests enhanced responses in LAdrKO mice during a glucagon tolerance test (250 μg/kg ip.). 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 post-prandial peaks in hepatic adropin expression. Rhythms of hepatic adropin expression appear to link rhythms in energy balance and cellular stress to the intracellular signal transduction pathways that drive the liver fasting response.
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