Neuronostatin Induces C‐FOS Response and Gluconeogenic Enzymes in HEPG2 Cells: A Potential Role of Neuronostatin in the Liver

Abstract

Hepatic glucose production (HGP) and output are regulated by a complex system of hormones, receptors, signaling mechanisms, glycolytic and gluconeogenic enzymes, and many overlapping transcription factors. The proteins involved in HGP are attractive targets for antidiabetic therapy, yet better pharmacological interventions are still needed for treatment. Therefore, it is critical to identify and characterize new targets within HGP regulation. We identified a novel peptide, neuronostatin, encoded in the somatostatin prohormone that exerts effects in the central nervous system, the heart, and the pancreas. Neuronostatin is produced in the delta cells of the pancreatic islets and plays an important role in maintaining glucose homeostasis through enhancing glucagon secretion from the α cell and reducing insulin release from the β cell. In male rats, a bolus injection of neuronostatin significantly increased blood glucose over 30 minutes after administration. Likewise, the peptide delayed glucose clearance and diminished the insulin response to hyperglycemia in a glucose tolerance test. Our group also identified the orphan GPCR, GPR107, as a cognate receptor for the peptide. GPR107 is expressed in numerous tissues, including the liver.In searching for the role of neuronostatin in hepatic physiology, we observed that hepatocellular carcinoma cell line HEPG2 expressed GPR107. Thus, we hypothesized that neuronostatin would elicit a biologic effect on the liver using HEPG2 cell line as in‐vitro model. We found that treatment of HEPG2 cells with neuronostatin significantly elevated cFos mRNA expression, indicating that HEPG2 cells respond to the peptide. In addition, neuronostatin induced expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase and glucose‐6‐phosphatase. These results indicate potential effects of neuronostatin on HGP, so we sought to determine if the effects of neuronostatin on blood glucose were due to increased glucagon secretion or due to a direct effect in the liver. In rats treated with a glucagon receptor antagonist, neuronostatin increased blood glucose, supporting a glucagon‐independent action on HGP. Thus, our results suggest that neuronostatin could play a physiologically relevant role in the liver and that GPR107 may be a new target in hepatic glucose production.Support or Funding InformationNational Institute of Health