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

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

doi:10.1016/j.celrep.2021.109301

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

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

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English
Article number	109301
Journal	Cell Reports
Volume	35
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2021.109301
State	Published - Jun 29 2021

Bibliographical note

Publisher Copyright:
© 2021

Funding

The authors wish to thank Drs. Richard Lee and Mark Graham of Ionis Pharmaceuticals, Carlsbad, CA for providing both the GABA-T and control antisense oligonucleotides and the UC Davis MMPC Energy Balance, Exercise, & Behavior Core ( NIH grant U24-DK092993 ) for performing energy expenditure and physical activity measurements by indirect respiratory calorimetry using CLAMS and assessing body composition by DEXA. This research was funded by the Arizona Biomedical Research Commission Early Stage Investigator Award (award no. ADHS14-082986 ; B.J.R.), American Heart Association Beginning Grant In Aid (award no. 15BGIA25090300 ; B.J.R.), Arizona Biomedical Research Commission Investigator Grant (award no. ADHS18-201472 ; B.J.R.), and the Cardiovascular Research (HLB) NIH T32 Training Grant (award no. T32HL007249 ; C.E.G.).

Funders	Funder number
DEXA
National Institutes of Health (NIH)	U24-DK092993
National Institutes of Health/National Institute of Environmental Health Sciences	P30ES006694
American the American Heart Association	ADHS18-201472, 15BGIA25090300, T32HL007249
University of California Davis
Arizona Biomedical Research Commission	ADHS14-082986

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

GABA
GABA shunt
GABA transaminase
NAFLD
NASH
Type 2 diabetes mellitus
hyperinsulinemia
insulin resistance
obesity

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.celrep.2021.109301

Cite this

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title = "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.",

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author = "Geisler, \{Caroline E.\} and Susma Ghimire and Bruggink, \{Stephanie M.\} and Miller, \{Kendra E.\} and Weninger, \{Savanna N.\} and Kronenfeld, \{Jason M.\} and Jun Yoshino and Samuel Klein and Duca, \{Frank A.\} and Renquist, \{Benjamin J.\}",

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doi = "10.1016/j.celrep.2021.109301",

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AU - Weninger, Savanna N.

AU - Kronenfeld, Jason M.

AU - Yoshino, Jun

AU - Klein, Samuel

AU - Duca, Frank A.

AU - Renquist, Benjamin J.

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KW - GABA transaminase

KW - NAFLD

KW - NASH

KW - Type 2 diabetes mellitus

KW - hyperinsulinemia

KW - insulin resistance

KW - obesity

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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