Melinjo seed extract increases adiponectin multimerization in physiological and pathological conditions

Melinjo seed extract (MSE) contains large amounts of polyphenols, including dimers of trans-resveratrol (e.g. gnetin C, L, gnemonoside A, B and D), and has been shown to potentially improve obesity. However, there is no clinical evidence regarding the anti-obesity effects of MSE, and its mechanisms are also unclear. We investigated the hypothesis that MSE supplementation increases the adiponectin (APN) multimerization via the up-regulation of disulfide bond A oxidoreductase-like protein (DsbA-L) under either or both physiological and obese conditions. To investigate the effect of MSE on the physiological condition, 42 healthy young volunteers were enrolled in a randomized, double-blind placebo-controlled clinical trial for 14 days. The participants were randomly assigned to the MSE 150 mg/day, MSE 300 mg/day or placebo groups. Furthermore, in order to investigate the effect of MSE on APN levels under obese conditions, we administered MSE powder (500 or 1000 mg/kg/day) to control-diet- or high-fat-diet (HFD)-fed C57BL/6 mice for 4 weeks. All participants completed the clinical trial. The administration of MSE 300 mg/day was associated with an increase in the ratio of HMW/total APN in relation to the genes regulating APN multimerization, including DsbA-L. Furthermore, this effect of MSE was more pronounced in carriers of the DsbA-L rs191776 G/T or T/T genotype than in others. In addition, the administration of MSE to HFD mice suppressed their metabolic abnormalities (i.e. weight gain, increased blood glucose level and fat mass accumulation) and increased the levels of total and HMW APN in serum and the mRNA levels of ADIPOQ and DsbA-L in adipose tissue. The present study suggests that MSE may exert beneficial effects via APN multimerization in relation to the induction of DsbA-L under both physiological and obese conditions.