The role of 3’,4’-dihydroxyphenyl-γ-valerolactone, the gut microbiota metabolite of (−)-epicatechin, in reducing insulin resistance

Background: Hydroxyphenyl-γ-valerolactones (HPVLs) are microbiota-derived metabolites of monomeric catechins and comprise about 33 % of total human catechin metabolites. HPVLs could therefore contribute to the previously reported beneficial effects of (−)-epicatechin (EC) on high-fat (HF) diet induced weight gain and insulin resistance (IR) in mice. Aims: Assess the bioavailability and metabolism of 3’,4’-dihydroxyphenyl-γ-valerolactone (34DHPVL) and determine its effects on IR, body weight gain, steatosis and hepatic gene expression changes when fed directly to mice on HF or low-fat (LF) diets. Methods: Male C57BL/6J mice were fed LF (10 % kcal) or HF (60 % kcal) diets with or without 20 mg/kg body weight (BW) supplementation of EC or 34DHPVL for 15-weeks. A fasted glucose tolerance test was performed at week-13 to assess IR. Plasma and liver lipids were quantified, and the effects on global gene expression assessed via RNA-sequencing analysis of liver tissue. Results: Gavaged 34DHPVL was highly bioavailable and present in plasma solely as sulfated and glucuronidated conjugates. 34DHPVL dietary supplementation reduced plasma glucose A.U.C (p-= 0.12) albeit non-significantly (ns), paradoxically increased plasma insulin (p-<-0.01) and liver lipids (ns) but had no effect on HF diet-induced BW gain. EC dietary supplementation improved insulin sensitivity (HOMA-IR, p-=-0.07), and mitigated HF diet-induced BW and liver weight gain and hepatic lipid accumulation (all p-<-0.05). Both EC and 34DHPVL protected against HF diet-induced increases in expression of genes involved in glucose production and increased expression of insulin signalling genes, but the effects of EC were much stronger. Conclusion: These data suggest that 34DHPVL may contribute modestly to the beneficial effects of EC consumption on HF-diet induced IR, but it is clear that the effects of the parent EC are stronger. 34DHPVL is not responsible for the mitigation of HF diet-induced BW gain caused by EC, which suggests that this effect is caused by EC conjugates