(P20-036-25) Roles of Blood GABA and Hepatic GABA Transaminase in Food Intake Suppression

Objectives: Previous studies showed that combining dietary γ-aminobutyric acid (GABA) with vigabatrin (Vig), a GABA transaminase (GABA-T) inhibitor, strongly suppressed food intake in obese mice. We hypothesized that this effect is primarily due to elevated blood GABA levels via GABA-T inhibition. This study aimed to: 1) establish a direct correlation between blood GABA levels and food intake suppression and 2) determine if hepatic GABA-T inhibition combined with dietary GABA reduces food intake, independent of Vig's brain effects.

Methods: Experiment (Exp) I: Lean mice on a basal diet were fasted for 24 h, starting at 10 am. One hour before refeeding, mice received PBS or Vig (250 mg/kg) injections and were fed either a control or 2% GABA diet. Food intake and blood samples were collected at 0.5 to 24 h post-refeeding. Exp II: Hepatic GABA-T knockdown was achieved using antisense oligonucleotides (ASO) targeting hepatic GABA-T mRNA. High-fat (HF)-diet-induced obese mice were divided into six groups and treated with ASO (12.5 mg/kg), Vig, or PBS with either a control HF or 2% GABA-HF diet for two weeks. Food intake were monitored daily, and blood GABA levels were analyzed using LC-MS/MS.

Results: In Ex I, 30 min post-refeeding, food intake (~1 g/mouse) was similar across groups. From 30 min to 6 h, the GABA+Vig group barely consumed any food, while the Vig or GABA alone group gradually increased their intake (~2 g/mouse by 6 h), similar to controls. Plasma GABA levels in the GABA+Vig group were significantly elevated at 30 min (167.0 µM vs. 0.03-32.2 µM in other groups, p < 0.05) and declined at 6 h. Plasma GABA levels negatively correlated with food intake (r = −0.3768, p = 0.001). In Exp II, ASO significantly reduced hepatic GABA-T mRNA expression and activity without affecting brain GABA-T. In the GABA-HF diet group, ASO or Vig reduced food intake compared to controls (1.6–1.7 vs. 2.0–2.1 g/day/mouse, p < 0.05). Plasma GABA levels were significantly higher in the GABA+ASO (62.1 µM) and GABA+Vig (22.2 µM) groups compared to controls (0.00–7.4 µM, p < 0.05).

Conclusions: Blood GABA levels are inversely correlated with food intake, and hepatic GABA-T inhibition alone with dietary GABA can suppress food intake, suggesting hepatic GABA-T as a novel obesity research target.

Funding Sources: Tojuro Iijima Foundation. Kobayashi Foundation. Grant-in-Aid for Scientific Research C (No.24K08746).