PT  - JOURNAL ARTICLE
AU  - Caroline. E. Geisler
AU  - Susma. Ghimire
AU  - Stephanie. M. Bruggink
AU  - Kendra E. Miller
AU  - Savanna. N. Weninger
AU  - Jason. M. Kronenfeld
AU  - Jun. Yoshino
AU  - Samuel. Klein
AU  - Frank. A. Duca
AU  - Benjamin. J. Renquist
TI  - A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
AID  - 10.1101/2020.04.02.022699
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.02.022699
4099  - http://biorxiv.org/content/early/2020/04/03/2020.04.02.022699.short
4100  - http://biorxiv.org/content/early/2020/04/03/2020.04.02.022699.full
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.