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

Geisler, C. Daniel; Ghimire, Susma; Bruggink, Stephanie; Miller, Kendra E.; Weninger, Savanna N.; Kronenfeld, Jason; Yoshino, Jun; Klein, Samuel; Duca, Frank A.; Renquist, Benjamin J.

doi:10.1016/j.celrep.2021.109301

Cited by 28 publications

(14 citation statements)

References 53 publications

(66 reference statements)

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“…In this context, it should be noted that GABA, the natural ligand of GABA A R, has been implicated in obesogenic pathways outside of the nervous system. Thus, hepatic synthesis of GABA, catalyzed by GABA-transaminase, is upregulated in obese mice and persons, and its inhibition improves both hyperphagy and diabetes in mice [ 59 ]. GABA is also increased in the interscapular BAT of obese mice, and its oral supplementation with the drinking water suffices to worsen glucose intolerance in the context of HFD [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

Anagnostopoulos

Motiño

et al. 2022

Cell Death Dis

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Acyl-coenzyme-A-binding protein (ACBP), also known as a diazepam-binding inhibitor (DBI), is a potent stimulator of appetite and lipogenesis. Bioinformatic analyses combined with systematic screens revealed that peroxisome proliferator-activated receptor gamma (PPARγ) is the transcription factor that best explains the ACBP/DBI upregulation in metabolically active organs including the liver and adipose tissue. The PPARγ agonist rosiglitazone-induced ACBP/DBI upregulation, as well as weight gain, that could be prevented by knockout of Acbp/Dbi in mice. Moreover, liver-specific knockdown of Pparg prevented the high-fat diet (HFD)-induced upregulation of circulating ACBP/DBI levels and reduced body weight gain. Conversely, knockout of Acbp/Dbi prevented the HFD-induced upregulation of PPARγ. Notably, a single amino acid substitution (F77I) in the γ2 subunit of gamma-aminobutyric acid A receptor (GABAAR), which abolishes ACBP/DBI binding to this receptor, prevented the HFD-induced weight gain, as well as the HFD-induced upregulation of ACBP/DBI, GABAAR γ2, and PPARγ. Based on these results, we postulate the existence of an obesogenic feedforward loop relying on ACBP/DBI, GABAAR, and PPARγ. Interruption of this vicious cycle, at any level, indistinguishably mitigates HFD-induced weight gain, hepatosteatosis, and hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

Anagnostopoulos

Motiño

et al. 2022

Cell Death Dis

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“…Damage to liver cells results in increased permeability of cell membranes, which leads to the entry of AST and ALT from the liver into the bloodstream. 20 The HFD triggered high ALT levels in the blood ( p < 0.05) while no significant effect was observed for the AST level ( p > 0.05). Notably, LJ, FLJ and GABA supplementation could effectively reduce the ALT levels.…”

Section: Resultsmentioning

confidence: 89%

“…Geisler et al found that hepatocyte GABA production (GABAtransaminase catalyzed synthesis) effectively regulates glucose regulation dysfunction and feeding behavior associated with obesity. 20 Moreover, previous studies have shown that oral treatment with GABA reduced the body weight gain, epididymal fat mass, and adipocyte size of HFD-fed mice, mainly due to the action of GABA on the peripheral GABA receptors, which inhibited insulin resistance and obesity by inhibiting obesityrelated inflammation and up-regulating Treg responses in vivo. 47 In addition, it can be seen in Fig.…”

Section: Gaba Attenuates Obesity Via Regulating Intestinal Flora In Micementioning

confidence: 99%

GABA and fermented litchi juice enriched with GABA promote the beneficial effects in ameliorating obesity by regulating the gut microbiota in HFD-induced mice

et al. 2023

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“…Glutaminase and glutamate decarboxylase play an important role in GABA synthesis, and hepatic synthesis of GABA, catalyzed by GAD, is upregulated in obese mice. Hepatic GAD inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia and improved glucose intolerance, as well as playing a positive role in improving NASH (Geisler et al, 2021). The results showed that AB23A could down‐regulate the expression of Gls and Gad1 mRNA and reduce blood ammonia levels.…”

Section: Discussionmentioning

confidence: 99%

Mechanical study of alisol B 23‐acetate on methionine and choline deficient diet‐induced nonalcoholic steatohepatitis based on untargeted metabolomics

Li,

Wang,

Wang

et al. 2023

Biomedical Chromatography

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Alisol B 23‐acetate (AB23A) has been demonstrated to have beneficial effects on nonalcoholic steatohepatitis (NASH). However, the mechanisms of AB23A on NASH remain unclear. This study aimed to investigate the mechanisms underlying the metabolic regulatory effects of AB23A on NASH. We used AB23A to treat mice with NASH, which was induced by a methionine and choline deficient (MCD) diet. We initially investigated therapeutic effect and resistance to oxidation and inflammation of AB23A on NASH. Subsequently, we performed untargeted metabolomic analyses and relative validation assessments to evaluate the metabolic regulatory effects of AB23A. AB23A reduced lipid accumulation, ameliorated oxidative stress and decreased pro‐inflammatory cytokines in the liver. Untargeted metabolomic analysis found that AB23A altered the metabolites of liver. A total of 55 differential metabolites and three common changed pathways were screened among the control, model and AB23A treatment groups. Further tests validated the effects of AB23A on modulating common changed pathway‐involved factors. AB23A treatment can ameliorate NASH by inhibiting oxidative stress and inflammation. The mechanism of AB23A on NASH may be related to the regulation of alanine, aspartate and glutamate metabolism, d‐glutamine and d‐glutamate metabolism, and arginine biosynthesis pathways.

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

Cited by 28 publications

References 53 publications

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

GABA and fermented litchi juice enriched with GABA promote the beneficial effects in ameliorating obesity by regulating the gut microbiota in HFD-induced mice

Mechanical study of alisol B 23‐acetate on methionine and choline deficient diet‐induced nonalcoholic steatohepatitis based on untargeted metabolomics

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