Neuronostatin induces gluconeogenic enzyme expression and glucose release in hepatocytes

Hepatic glucose production (HGP) is 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, and thus it is critical to identify and characterize new targets within the regulation of HGP. We identified a novel peptide, neuronostatin (NST), encoded in the somatostatin preprohormone that exerts its effects in the central nervous system, the heart, and the pancreas. NST 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 NST 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 NST in hepatic physiology, we observed that hepatocellular carcinoma cell line HEPG2 expressed GPR107. Thus, we hypothesized that NST would elicit hepatic glucose production. We found that treatment of HEPG2 cells with NST significantly elevated cFos mRNA expression, indicating that HEPG2 cells respond to the peptide. In addition, NST induced expression of key gluconeogenic enzymes and enhanced glucose release in HepG2 cells. In vivo, antagonism of the glucagon receptor in rats did not attenuate elevated blood glucose levels in response to treatment of NST, supporting a direct, glucagon-independent action of NST on HGP. Thus, our results suggest that NST could play a physiologically relevant role in the liver and that GPR107 could be a potential new target to modulate HGP. National Institute of Health (NIH) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.