Researchers synthesized complex menthyl esters and revealed the mechanism by which they interact with the liver X receptor. Researchers developed menthyl esters that have significant anti-inflammatory and anti-obesity effects, potentially offering new treatments for chronic inflammatory conditions and metabolic disorders.

Recent therapeutic advances and commercial successes have often been driven by modified derivatives of natural products. Menthol, a naturally occurring cyclic monoterpene alcohol, is found in a variety of plants, particularly members of the mint family such as peppermint and spearmint. It is widely used in confectionery, chewing gum, and oral care products. It should be noted that menthol also has important medicinal properties, including analgesic, anti-inflammatory, and anti-cancer effects.

In a recent study, a group of researchers led by Professor Gen-Ichiro Arimura from the Department of Biological Sciences and Technology, Tokyo University of Science, Japan, developed and investigated valine (MV) and isoleucine (MI) menthyl esters. They are obtained by replacing the hydroxyl group of menthol with valine and isoleucine, respectively.

The results of their research were recently published in a journal. Immunology Sharing the motivation behind this work, Professor Arimura says: “I have always been interested in the functional components of plants that contribute to human health. The discovery of new molecules from natural materials inspired our research group to develop these amino acid derivatives of menthol.”

Anti-inflammatory properties of menthyl ethers

The researchers began by synthesizing menthyl esters of six amino acids characterized by less reactive side chains. They then evaluated the properties of these esters using in vitro cell line studies. Finally, they conducted experiments on mice to investigate the effects of these compounds under induced disease conditions. The exceptional anti-inflammatory profiles of MV and MI were determined by assessing tumor necrosis factor-α (Tnf) transcript levels in stimulated macrophage cells. In particular, both MV and MI outperformed menthol in the anti-inflammatory test. RNA sequencing analysis showed that 18 genes involved in inflammatory and immune responses were effectively suppressed.

Excited by their findings, the researchers went further to investigate the mechanism of action of menthyl ethers. They found that the liver X receptor (LXR), an intracellular nuclear receptor, plays a key role in the anti-inflammatory effect and that this is independent of the cold-sensitive transient receptor TRPM8, which primarily senses menthol. By examining LXR-dependent activation of MV and MI, they found that the Scd1 gene, central to lipid metabolism, is regulated by LXR. In addition, the anti-inflammatory effects in mice with induced intestinal colitis were further confirmed by LXR-dependent suppression of Tnf and IL6 gene transcript levels by MV or MI.

Potential anti-obesity effects

Based on the discovery of the intracellular mechanism of LXR-SCD1, Professor Arimura and his team hypothesized that menthyl esters have anti-obesity properties. They found that these esters suppress adipogenesis, the accumulation of fat in the mitotic clonal expansion phase, especially in 3T3-L1 adipocyte cells. Animal studies showed that diet-induced obesity in mice was reduced and adipogenesis was inhibited.

Menthyl ethers have unique advantages over other anti-inflammatory or anti-obesity compounds currently under investigation or in use. Their specific mechanisms of action that contribute to their dual anti-inflammatory and anti-obesity effects distinguish them from other compounds and may make them particularly effective in treating both inflammatory conditions and metabolic disorders. They may benefit certain populations, such as those with chronic inflammatory diseases, metabolic syndrome, or obesity-related complications.

“Although this study focused on their function and mechanism of action in diseases modeled by inflammation and obesity, we expect these compounds to also be effective against a wide range of lifestyle-related diseases caused by the metabolic syndrome, such as diabetes and hypertension, as well as allergic symptoms,” says Professor Arimura optimistically.

In conclusion, this study highlights the importance and value of versatile molecules derived from natural substances. Future research involving these novel and superior menthyl esters may lead to the development of therapeutic compounds for the increasingly important health problems associated with obesity and inflammatory conditions.