Gamma-aminobutyric acid (
GABA) is a natural
amino acid with
antioxidant activity and is often considered to have therapeutic potential against
obesity.
Obesity has long been linked to ROS and ER stress, but the effect of
GABA on the ROS-associated ER stress axis has not been thoroughly explored. Thus, in this study, the effect of
GABA and fermented Curcuma longa L. extract enriched with
GABA (FCLL-
GABA) on the ROS-related ER stress axis and
inositol-requiring transmembrane
kinase/
endoribonuclease 1α (IRE1α) sulfonation were examined with the HFD model to determine the underlying anti-
obesity mechanism. Here,
GABA and FCLL-
GABA supplementations significantly inhibited the
weight gain in HFD fed mice. The
GABA and FCLL-
GABA supplementation lowered the expressions of adipogenic
transcription factors such as
PPAR-γ, C/EBPα, FAS, and
SREBP-1c in white adipose tissue (WAT) and liver from HFD-fed mice. The enhanced hyper-nutrient dysmetabolism-based
NADPH oxidase (Nox) 4 and the resultant IRE1α sulfonation-RIDD-SIRT1 decay under HFD conditions were controlled with
GABA and FCLL-
GABA. Notably,
GABA and FCLL-
GABA administration significantly increased AMPK and
sirtuin 1 (
SIRT1) levels in WAT of HFD-fed mice. These significant observations indicate that ER-localized Nox4-induced IRE1α sulfonation results in the decay of
SIRT1 as a novel mechanism behind the positive implications of
GABA on
obesity. Moreover, the investigation lays a firm foundation for the development of FCLL-
GABA as a functional ingredient.