Nobiletin ameliorates hepatic insulin resistance by modulating the gut-liver axis.

Insulin resistance (IR) is a core pathological feature of type 2 diabetes mellitus (T2DM), with hepatic IR serving as a hallmark of systemic IR. Nobiletin (NOB) shows great potential in exerting hypoglycemic effects and improving IR; however, its molecular mechanisms remain incompletely elucidated. This study aims to investigate the molecular mechanisms by which nobiletin (NOB) ameliorates hepatic IR. Our results demonstrated that NOB effectively ameliorated IR in both high-fat diet/streptozotocin (HFD/STZ)-induced mice and palmitic acid (PA)-treated HepG2 cells. NOB administration improved dyslipidemia and attenuated histopathological damage in mouse liver tissue. Additionally, NOB reduced lipid accumulation in both the mouse liver and HepG2 cells by inhibiting de novo lipogenesis (DNL) and free fatty acids (FFA) uptake while enhancing mitochondrial fatty acid β-oxidation (FAO). Moreover, NOB suppressed hepatic gluconeogenesis by activating the PI3K/AKT/FOXO1 signaling pathway. NOB also enhanced the intestinal barrier function, as evidenced by the upregulation of ZO-1, Claudin-1, and Occludin proteins. Furthermore, NOB increased gut microbiome diversity, reduced the F/B ratio, and enriched beneficial taxa, including Verrucomicrobia, Lachnospiraceae, and Akkermansia muciniphila, thereby ameliorating gut microbiota dysbiosis. This study pioneers the elucidation of the cooperative mechanisms by which NOB ameliorates IR through the gut-liver axis and multi-target regulation of hepatic lipid metabolism, establishing a foundation for the development of NOB-derived nutraceuticals and pharmaceuticals.