Ellagic Acid and Its Microbial Metabolite Urolithin A Alleviate Diet‐induced Insulin Resistance in Mice

SCOPE: We aimed at evaluating the effect of dietary ellagic acid (EA) and its microbial metabolite urolithin A (UA) on glucose metabolism and insulin resistance (IR) in mice with diet-induced IR. METHODS AND RESULTS: DBA2J mice were fed a high fat/high sucrose diet (HF/HS) for 8 weeks to induce IR and then 0.1% EA, UA, or EA and UA combined (EA+UA) were added to the HF/HS-diet for another 8 weeks. UA significantly decreased fasting glucose and increased serum adiponectin compared with HF/HS-controls. During intraperitoneal insulin tolerance test, EA+UA significantly improved insulin-mediated glucose lowering effects at 15 and 120 min and reduced blood triglycerides compared with HF/HS-controls. Serum free fatty acids were significantly decreased by EA, UA and EA+UA. We observed differential expression of genes related to mitochondrial function by EA, UA and EA+UA in liver and skeletal muscle. Primary hepatocytes from IR-mice had higher proton leak, basal and ATP-linked oxygen consumption rates compared with healthy controls. EA and EA+UA but not UA reduced the proton leak in hepatocytes from IR-mice. CONCLUSION: EA and UA induced different metabolic benefits in HF/HS diet induced IR mice. The effects of EA and UA on mitochondrial function suggest a potentially novel mechanism modulating metabolism. This article is protected by copyright. All rights reserved.