Long-term Effects of Gamma-aminobutyric Acid on Lipid Metabolism, Inflammatory Responses, and Insulin Sensitivity in 3T3-L1 Adipocytes

Interest in gamma-aminobutyric acid (GABA) as a metabolic modulator has increased, yet its direct role in adipocyte function remains unclear. This study assessed the prolonged effects of GABA on lipid metabolism, inflammatory responses, and insulin sensitivity in an in vitro adipocyte model. Adipocytes were treated with GABA for up to 21 days. GABA significantly reduced intracellular lipid accumulation at high concentrations, with approximately a 20% decrease observed at 1000 µM, without inducing cytotoxicity. During adipogenesis, interleukin 6 (IL-6) secretion increased in a time-dependent manner, whereas tumor necrosis factor alpha (TNF-α) levels remained unchanged. GABA markedly suppressed IL-6 secretion in fully mature adipocytes, demonstrating anti-inflammatory activity. Stage-specific analysis revealed that GABA treatment during the early differentiation phase (D0–D3) was sufficient to inhibit lipid accumulation and IL-6 release, with effects comparable to treatment throughout the entire adipogenesis period, highlighting the critical role of early differentiation in GABA-mediated inhibition. Mature adipocytes exhibited insulin resistance, as indicated by impaired insulin-stimulated glucose uptake. Long-term GABA treatment enhanced functional insulin responsiveness under insulin-stimulated conditions, while direct GABA exposure enhanced insulin-stimulated glucose uptake in mature adipocytes. Collectively, these findings suggest that GABA reduces intracellular lipid accumulation and inflammation and improves functional insulin responsiveness in this in vitro adipocyte model.