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In this study, we investigated the effects of GABA on high\u2010fat diet (HFD)\u2010induced hepatic metabolic abnormalities and liver insulin resistance in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male C57BL\/6J mice were fed a normal chow diet, HFD or HFD combined with GABA in drinking water for 14\u2009weeks; the insulin sensitivity and inflammation signalling molecules such as toll\u2010like receptor 4 (TLR4), nuclear factor kappa B (NF\u2010\u03baB) and TNF\u2010\u03b1 were evaluated. Moreover, the effect of GABA on the above inflammatory signalling molecules and electrophysiology was explored in macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Oral GABA treatment attenuated HFD\u2010induced liver steatosis and increased hepatic insulin sensitivity. This was associated with inactivation of Kupffer cells (KCs) and decreased production of hepatic TNF\u2010\u03b1. GABA treatment significantly suppressed TLR4\/NF\u2010\u03baB activation in livers of HFD\u2010fed mice. Consistently, in vitro studies showed that GABA\u2010attenuated palmitate\u2010induced upregulation of TLR4 signalling and TNF\u2010\u03b1 production in the macrophage. Furthermore, conditioned medium from macrophage cells treated with palmitate significantly attenuated insulin\u2010stimulated protein kinase B (Akt) activation in HepG2 cells. However, this did not occur in the conditioned medium from palmitate\u2010treated 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\u2010induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx and TNF\u2010\u03b1 production.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GABA ameliorates HFD\u2010induced hepatic insulin resistance by suppressing KCs activation and its production and secretion of inflammatory cytokines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.16556","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T04:49:14Z","timestamp":1751604554000},"page":"5085-5098","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp>GABA<\/scp>\n                    ameliorates diet\u2010induced hepatic steatosis and insulin resistance by 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