A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity

Caroline E. Geisler, Susma Ghimire, Stephanie M. Bruggink, Kendra E. Miller, Savanna N. Weninger, Jason M. Kronenfeld, Jun Yoshino, Samuel Klein, Frank A. Duca, Benjamin J. Renquist

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR), T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.

Original languageEnglish (US)
Article number109301
JournalCell Reports
Volume35
Issue number13
DOIs
StatePublished - Jun 29 2021

Keywords

  • GABA
  • GABA shunt
  • GABA transaminase
  • NAFLD
  • NASH
  • Type 2 diabetes mellitus
  • hyperinsulinemia
  • insulin resistance
  • obesity

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity'. Together they form a unique fingerprint.

Cite this