@article{9a2acb1b8c834a75be65fa532e2c77c2,
title = "Hepatocyte membrane potential regulates serum insulin and insulin sensitivity by altering hepatic GABA release",
abstract = "Hepatic lipid accumulation in obesity correlates with the severity of hyperinsulinemia and systemic insulin resistance. Obesity-induced hepatocellular lipid accumulation results in hepatocyte depolarization. We have established that hepatocyte depolarization depresses hepatic afferent vagal nerve firing, increases GABA release from liver slices, and causes hyperinsulinemia. Preventing hepatic GABA release or eliminating the ability of the liver to communicate to the hepatic vagal nerve ameliorates the hyperinsulinemia and insulin resistance associated with diet-induced obesity. In people with obesity, hepatic expression of GABA transporters is associated with glucose infusion and disposal rates during a hyperinsulinemic euglycemic clamp. Single-nucleotide polymorphisms in hepatic GABA re-uptake transporters are associated with an increased incidence of type 2 diabetes mellitus. Herein, we identify GABA as a neuro-hepatokine that is dysregulated in obesity and whose release can be manipulated to mute or exacerbate the glucoregulatory dysfunction common to obesity.",
keywords = "GABA, GABA transporter, GABA-transaminase, NAFLD, Type 2 diabetes, hyperinsulinemia, insulin resistance, membrane potential, obesity",
author = "Geisler, {Caroline E.} and Susma Ghimire and Chelsea Hepler and Miller, {Kendra E.} and Bruggink, {Stephanie M.} and Kentch, {Kyle P.} and Higgins, {Mark R.} and Banek, {Christopher T.} and Jun Yoshino and Samuel Klein and Renquist, {Benjamin J.}",
note = "Funding Information: The authors wish to thank Dr. Scott Sternson at the Howard Hughes Medical Institute (Ashburn, VA, USA) for 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; the Penn Vector Core (University of Pennsylvania) for design and synthesis of the AAVs used in this study; and Drs. Ralph Fregosi, Masoud Ghamari-Langroudi, and Richard Levine for guidance on experimental models and electrophysiology. This research was funded by the Arizona Biomedical Research Commission Early Stage Investigator Award (No. ADHS14-082986 to B.J.R.), American Heart Association Beginning Grant in Aid (Award No. 15BGIA25090300 to B.J.R.), Arizona Biomedical Research Commission Investigator Grant (Award No. ADHS18-201472 to B.J.R.), and the Cardiovascular Research (HLB) NIH T32 Training Grant (Award No. T32HL007249 to C.E.G. and S.M.B.). C.E.G. conceived experimental design and project conceptualization, performed experiments and wet lab analyses, wrote initial draft of manuscript, generated figures, and reviewed and edited the manuscript. S.G. performed experiments and wet lab analyses and reviewed and edited the manuscript. C.H. performed experiments and wet lab analyses and reviewed and edited the manuscript. K.E.M. performed experiments and wet lab analyses and reviewed and edited the manuscript. S.M.B. performed experiments and wet lab analyses and reviewed and edited the manuscript. K.P.K. performed experiments and wet lab analyses and reviewed and edited the manuscript. M.R.H. developed electrophysiology methodology, performed experiments, and reviewed the manuscript. C.T.B. performed experiments and wet lab analyses and reviewed and edited the manuscript. J.Y. performed studies to assess glucose homeostasis, collected human liver samples, performed RNA sequencing, and reviewed and edited the manuscript. S.K. performed studies to assess glucose homeostasis, collected human liver samples, performed RNA sequencing, and reviewed and edited the manuscript. B.J.R. conceived experimental design and project conceptualization, performed surgeries, analyzed statistics, and reviewed and edited the manuscript. The results presented in this paper have resulted in patent cooperation treaty Application No. 62/511,753 and 62/647,468: METHODS AND COMPOSITIONS FOR REGULATING GLUCOSE HOMEOSTASIS, which has been licensed by Livendocrine, LLC founded by Benjamin Renquist. Funding Information: The authors wish to thank Dr. Scott Sternson at the Howard Hughes Medical Institute (Ashburn, VA, USA) for 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; the Penn Vector Core (University of Pennsylvania) for design and synthesis of the AAVs used in this study; and Drs. Ralph Fregosi, Masoud Ghamari-Langroudi, and Richard Levine for guidance on experimental models and electrophysiology. This research was funded by the Arizona Biomedical Research Commission Early Stage Investigator Award (No. ADHS14-082986 to B.J.R.), American Heart Association Beginning Grant in Aid (Award No. 15BGIA25090300 to B.J.R.), Arizona Biomedical Research Commission Investigator Grant (Award No. ADHS18-201472 to B.J.R.), and the Cardiovascular Research (HLB) NIH T32 Training Grant (Award No. T32HL007249 to C.E.G. and S.M.B.). Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = jun,
day = "29",
doi = "10.1016/j.celrep.2021.109298",
language = "English (US)",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}