Melinjo-derived Gnetin C restores metabolic balance via dual adipose and hepatic effects in high-fat diet mice

TL;DR

Gnetin C, a compound from Melinjo seeds, improves metabolic health in obese mice by acting on both fat and liver tissues.

Contribution

Gnetin C is identified as a dual-acting compound that restores metabolic balance through adipose and hepatic mechanisms.

Findings

Gnetin C improves body weight and fasting glucose in high-fat diet-fed mice.

It enhances adiponectin multimerization and suppresses fat accumulation via the PPARγ-DsbA-L axis.

Gnetin C modulates hepatic Sirt1 and FGF21 signaling to improve metabolic outcomes.

Abstract

Multi-organ regulation underlies metabolic health, especially in the context of adipose-liver dysfunction during obesity. Previous findings identified Melinjo seed extract (MSE) as a promising modulator of metabolic disorders, although its active component remained unknown. Gnetin C, a trans-resveratrol dimer from MSE, likely serves as the key factor, yet its direct metabolic role remains unclear. Here, Gnetin C was administered to high-fat diet (HFD)-fed mice, which significantly improved body weight and fasting glucose, attributed to enhanced adiponectin (APN) multimerization. In adipose tissue, Gnetin C directly promotes APN multimerization and suppresses fat accumulation by up-regulating the PPARγ-DsbA-L axis, while concurrently modulating hepatic Sirt1, which may contribute to increased FGF21 production. This paracrine FGF21 signaling, suggested by elevated Fgfr1 in hepatocytes and βKlotho in adipocytes, further augments APN multimerization. These findings underscore the importance of a multi-tissue approach to obesity management and position Gnetin C as an integrative therapeutic candidate, restoring metabolic balance via dual adipose and hepatic effects in HFD mice.

The online version contains supplementary material available at 10.1038/s41598-025-25705-x.

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