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Publication
A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of
obesity.
Authors Geisler CE, Ghimire S, Bruggink SM, Miller KE, Weninger SN, Kronenfeld JM,
Yoshino J, Klein S, Duca FA, Renquist BJ
Submitted By Submitted Externally on 3/9/2022
Status Published
Journal Cell reports
Year 2021
Date Published 6/1/2021
Volume : Pages 35 : 109301
PubMed Reference 34192532
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.




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