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

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 35 Issue 13 Pg. 109301 (06 29 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34192532 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Biomarkers
• gamma-Aminobutyric Acid
• 4-Aminobutyrate Transaminase
• Glucose

Topics

• 4-Aminobutyrate Transaminase (metabolism)
• Animals
• Biomarkers (metabolism)
• Diet, High-Fat
• Energy Metabolism
• Feeding Behavior
• Glucose (metabolism)
• Glucose Clamp Technique
• Homeostasis
• Humans
• Hyperinsulinism (complications, metabolism, physiopathology)
• Hyperphagia (complications, metabolism, physiopathology)
• Insulin Resistance
• Liver (innervation, metabolism, physiopathology)
• Male
• Mice, Inbred C57BL
• Mice, Obese
• Obesity (complications, metabolism, physiopathology)
• Vagotomy
• Vagus Nerve (physiopathology)
• gamma-Aminobutyric Acid (metabolism)
• Mice