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

Subhashis Banerjee, Sarbani Ghoshal, Joseph R. Stevens, Kyle S. McCommis, Su Gao, Mauricio Castro-Sepulveda, Maria L. Mizgier, Clemence Girardet, K. Ganesh Kumar, Jose E. Galgani, Michael L. Niehoff, Susan A. Farr, Jinsong Zhang, Andrew A. Butler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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 remain poorly defined. Using surveys of Gene Expression Omnibus data sets, we confirm that fasting suppresses liver adropin expression in lean C57BL/6J (B6) mice. However, circadian rhythm data are inconsistent. In lean mice, caloric restriction (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 up-regulates adropin expression and induces rhythms correlating with cellular stress-response pathways. Furthermore, adropin expression correlates positively with 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 cAMP-dependent protein kinase A (PKA) signaling pathways also suggests enhanced responses in LAdrKO mice during a glucagon tolerance test (250 mg/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.

Original languageEnglish
Pages (from-to)13753-13768
Number of pages16
JournalJournal of Biological Chemistry
Volume295
Issue number40
DOIs
StatePublished - 2 Oct 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.

Fingerprint

Dive into the research topics of 'Hepatocyte expression of the micropeptide adropin regulates the liver fasting response and is enhanced by caloric restriction'. Together they form a unique fingerprint.

Cite this