Fish oil reduces intestinal fat absorption by promoting lacteal junction zippering via GPR120-VEGFR3-MLCK pathway

Diet-induced obesity can be improved by reducing intestinal fat absorption. Fish oil, enriched in n-3 PUFAs such as DHA and EPA, has shown promise in weight reduction. However, the role of fish oil in regulating intestinal fat absorption and the possible underlying mechanism remains largely unknown.

The aim of this study was to understand the mechanism underlying the fish oil elicited anti-obesity effects.

HFD-fed mice were subjected to fish oil and lymphatic endothelial cells (LECs) were treated with DHA or EPA. The intestinal fat absorption, the lacteal zipper-like junctions, and the involvement of GPR120-VEGFR3-MLCK pathway were assessed.

We found that fish oil gavage suppressed intestinal fat absorption associated with elevated proportion of lacteal zipper-like junctions and decreased expression of VEGFR3 in mice jejunum. Meanwhile, inhibition of VEGFR3 signaling in HFD-fed mice enhanced zipper-like junctions in jejunal lacteal to reduce fat absorption and combat obesity. In addition, DHA and EPA increased the proportion of zipper-like junctions via downregulation of VEGFR3 signaling in PA-treated LECs. However, activation of VEGFR3 signaling with VEGFC or inhibition of GPR120 with AH-7614 totally blocked the elevation of zipper-like junctions induced by DHA and EPA. Furthermore, DHA and EPA inhibited MLCK signaling in a GPR120-VEGFR3 dependent manner and inhibition of MLCK mimicked the promotive effects of DHA and EPA on zipper-like junctions. These in vitro results suggested that DHA and EPA increased the proportion of zipper-like junctions in PA-treated LECs through the GPR120-VEGFR3-MLCK signaling pathway. Finally, fish oil supplementation reduced intestinal fat absorption, promoted lacteal zipper-like junctions, enhanced GPR120 expression, inhibited VEGFR3 expression and MLCK signaling.

Overall, these findings showed for the first time that fish oil reduced intestinal fat absorption by promoting lacteal junctions zippering via GPR120-VEGFR3-MLCK pathway.