TY - JOUR
T1 - A critical role of hepatic GABA in the metabolic dysfunction and hyperphagia of obesity
AU - Geisler, Caroline E.
AU - Ghimire, Susma
AU - Bruggink, Stephanie M.
AU - Miller, Kendra E.
AU - Weninger, Savanna N.
AU - Kronenfeld, Jason M.
AU - Yoshino, Jun
AU - Klein, Samuel
AU - Duca, Frank A.
AU - Renquist, Benjamin J.
N1 - Publisher Copyright:
© 2021
PY - 2021/6/29
Y1 - 2021/6/29
N2 - 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.
AB - 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.
KW - GABA
KW - GABA shunt
KW - GABA transaminase
KW - NAFLD
KW - NASH
KW - Type 2 diabetes mellitus
KW - hyperinsulinemia
KW - insulin resistance
KW - obesity
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U2 - 10.1016/j.celrep.2021.109301
DO - 10.1016/j.celrep.2021.109301
M3 - Article
C2 - 34192532
AN - SCOPUS:85108886691
SN - 2211-1247
VL - 35
JO - Cell Reports
JF - Cell Reports
IS - 13
M1 - 109301
ER -
