Characterizing the pathway utilized by enterolactone and its metabolic precursor matairesinol to promote Glut4-dependent glucose uptake in 3T3-L1 adipocytes

Type-2 diabetes (T2D) is characterized by chronic insulin resistance and resultant fasting hyperglycemia. This is largely attributable to lifestyle factors like chronic over-nutrition, obesity, and excess abdominal adiposity. Research has shown an inverse association between habitual coffee consumption (both regular and decaffeinated) and T2D risk, suggesting that there may be protective effects elicited from certain chemical components of the beverage 1. Matairesinol (ML) is chemically classified as a lignan and is naturally occurring in coffee. It has been shown to inhibit the body weight gain and increase in fat mass commonly associated with high-fat diet-induced T2D2,3. ML and one of its gut microbial metabolites, enterolactone (ENL) (Fig. 1), have demonstrated the ability to promote glucose uptake in skeletal muscle3. ENL has also been found to inhibit hepatic triacylglycerol uptake and adipogenesis in adipocytes4. Furthermore, the presence of lignan metabolites in urine is associated with a lower risk of developing T2D5,6. Triacylglycerol uptake inhibition necessitates that ATP demand be met by the metabolism of alternative substrates. Given that glucose is generally the preferred substrate of ATP production, it is plausible that ML and ENL may attenuate T2D pathogenesis by promoting glucose uptake in both skeletal muscle and adipose tissues.