Hepatocyte Membrane Potential Regulates Serum Insulin and Insulin Sensitivity by Altering Hepatic GABA Release

Abstract

The degree of hepatic lipid accumulation in obesity directly correlates with the severity of hyperinsulinemia and systemic insulin resistance. Here, we propose a mechanism that explains this associative link, whereby, hepatic steatosis dysregulates glucose and insulin homeostasis. Obesity-induced lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing and diet induced obesity increases hepatic GABA release in mice. Hepatic GABA release decreases hepatic afferent vagal nerve activity to stimulate pancreatic insulin release and decreases insulin sensitivity. Surgically eliminating the hepatic vagal nerve signaling, preventing hepatic GABA synthesis, or limiting hepatic GABA export ameliorates hyperinsulinemia and insulin resistance in diet-induced obese mice. This work establishes that limiting hepatocyte GABA production or release may mute the glucoregulatory dysfunction common to obesity. Transaminase, Aspartate CEG -Experimental design and project conceptualization, performed experiments and wet lab analyses, wrote initial draft of manuscript, generated figures, reviewed and edited manuscript. CH -Performed experiments and wet lab analyses, reviewed and edited manuscript. SG -Performed experiments and wet lab analyses, reviewed and edited manuscript. MRH -Developed electrophysiology methodology and performed experiments, reviewed manuscript. RFF -Developed electrophysiology methodology, reviewed and edited manuscript. BJR -Experimental design and project conceptualization, performed surgeries and experiments, analyzed statistics, reviewed and edited manuscript. Acknowledgments:The authors wish to thank Dr. Scott Sternson at the Howard Hughes Medical Institute, Ashburn, VA., for kindly providing the PSEM89S ligand used in these studies, Ken Pendarvis at the University of Arizona for analyzing aspartate release from our ex vivo hepatic slice culture model by liquid chromatography-mass spectrometry, The Mayo Clinic Metabolomics Regional Core for performing the initial mass spectrophotometry analysis of media from our ex vivo hepatic slice culture model using their neurotransmitter panel to identify potential hepatocyte released signaling molecules, and Drs. Masoud Ghamari-Langroudi and Richard Levine for guidance on experimental models and electrophysiology.

Limited Defense of Liver Energy Status in Rats Susceptible to Diet-induced Obesity

“…Recognizing the limitations of the experiments described here, the results are consistent with studies reporting reduced liver energy status in diet-induced and genetically obese animals (25–28) and suggest that such a deficit in liver energy metabolism may underlie the susceptibility to diet-induced obesity. Co-administration of a fatty acid oxidation inhibitor and 2,5-AM, which in doses that are without effect alone, synergistically decreases liver energy status and increases food intake (19).…”