GABA ameliorates diet-induced hepatic steatosis and insulin resistance by inhibiting macrophage activation.

BACKGROUND

Obesity-associated fatty liver and hepatic insulin resistance are risk factors for impaired glucose tolerance and type 2 diabetes. In this study, we investigated the effects of GABA on high-fat diet (HFD)-induced hepatic metabolic abnormalities and liver insulin resistance in mice.

METHODS

Male C57BL/6J mice were fed a normal chow diet, HFD or HFD combined with GABA in drinking water for 14 weeks; the insulin sensitivity and inflammation signalling molecules such as toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) and TNF-α were evaluated. Moreover, the effect of GABA on the above inflammatory signalling molecules and electrophysiology was explored in macrophages.

RESULTS

Oral GABA treatment attenuated HFD-induced liver steatosis and increased hepatic insulin sensitivity. This was associated with inactivation of Kupffer cells (KCs) and decreased production of hepatic TNF-α. GABA treatment significantly suppressed TLR4/NF-κB activation in livers of HFD-fed mice. Consistently, in vitro studies showed that GABA-attenuated palmitate-induced upregulation of TLR4 signalling and TNF-α production in the macrophage. Furthermore, conditioned medium from macrophage cells treated with palmitate significantly attenuated insulin-stimulated protein kinase B (Akt) activation in HepG2 cells. However, this did not occur in the conditioned medium from palmitate-treated macrophages in the presence of GABA. Electrophysiological studies in macrophages showed that GABA evokes GABA currents and hyperpolarized the membrane potential. This membrane hyperpolarizing inhibitory effect is associated with decreased palmitate-induced Ca2+ influx and TNF-α production.

CONCLUSIONS

GABA ameliorates HFD-induced hepatic insulin resistance by suppressing KCs activation and its production and secretion of inflammatory cytokines.