Abstract

Obesity-associated adipocyte dysfunction promotes chronic inflammation, insulin resistance, and dysregulated lipolysis, contributing to metabolic disorders. This study addresses the unclear mechanisms of gamma-aminobutyric acid (GABA) in adipocytes by investigating its coordinated effects on three core metabolic pathways: inflammation, insulin resistance, and lipolysis. We utilized a palmitic acid (PA)-induced adipocyte dysfunction model in 3T3-L1 cells. Results showed that 800 µM PA for 24 hours induced insulin resistance and increased IL-6 and TNF-α secretion in mature 3T3-L1 adipocytes (Day 9). GABA treatment (500–1,000 µM) for nine days effectively prevented PA-induced insulin resistance, as insulin-stimulated glucose uptake was significantly improved. These high doses of GABA also reduced PA-induced IL-6 and TNF-α release. Regarding lipolysis, PA directly increased glycerol release and weakened insulin’s ability to suppress lipolysis. GABA (250–1,000 µM) dose-dependently reduced glycerol release and restored insulin’s anti-lipolytic effect in PA-treated adipocytes. GABA’s anti-inflammatory activity was further confirmed in RAW macrophages, where its dose-dependently inhibited nitric oxide (NO) production induced by 1 µg/mL lipopolysaccharide (LPS). However, its inhibitory effect on NO release in adipocytes was unclear, likely due to the low NO levels in LPS-treated adipocytes. In conclusion, although only high concentrations of GABA attenuated PA-induced adipocyte dysfunction through coordinated regulation of insulin signaling, inflammation, and lipolysis in cultured cells, these findings warrant further investigation into the potential of GABA and/or GABA receptor agonists in obesity-related metabolic dysfunction.

Key words: GABA, Pro-inflammatory cytokine, Insulin resistance, 3T3-L1 adipocytes, Obesity