RT Journal Article
SR Electronic
T1 A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.02.022699
DO 10.1101/2020.04.02.022699
A1 Caroline. E. Geisler
A1 Susma. Ghimire
A1 Stephanie. M. Bruggink
A1 Kendra E. Miller
A1 Savanna. N. Weninger
A1 Jason. M. Kronenfeld
A1 Jun. Yoshino
A1 Samuel. Klein
A1 Frank. A. Duca
A1 Benjamin. J. Renquist
YR 2020
UL http://biorxiv.org/content/early/2020/04/03/2020.04.02.022699.abstract
AB Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and 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, 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.