| Summary: | Interruptins A and B exhibited anti-diabetic, anti-inflammatory, and anti-oxidative effects. This study aimed to investigate the therapeutic ability of extract enriched by interruptins A and B (EEI) from an edible fern <i>Cyclosorus terminans</i> on insulin resistance and non-alcoholic fatty liver disease (NAFLD) in a high-fat diet (HFD)-induced obese rats and elucidate their possible mechanisms. HFD-induced obese rats were treated with EEI for 2 weeks. Real-time polymerase chain reaction (PCR) was used to examine the molecular basis. We found that EEI supplementation significantly attenuated body and liver weight gain, glucose intolerance, and insulin resistance. Concurrently, EEI increased liver and soleus muscle glycogen storage and serum high-density lipoprotein (HDL) levels. EEI also attenuated NAFLD, as indicated by improving liver function. These effects were associated with enhanced expression of insulin signaling genes (<i>Slc2a2, Slc2a4, Irs1</i> and <i>Irs2</i>) along with diminished expression of inflammatory genes (<i>Il6</i> and <i>Tnf</i>). Furthermore, EEI led to the suppression of lipogenesis genes, <i>Srebf1</i> and <i>Fasn</i>, together with an increase in fatty acid oxidation genes, <i>Ppara</i> and <i>Cpt2</i>, in the liver. These findings suggest that EEI could ameliorate HFD-induced insulin resistance and NAFLD via improving insulin signaling pathways, inflammatory response, lipogenesis, and fatty acid oxidation.
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