Fighting fat and inflammation: scientists have developed new compounds

Modified derivatives of natural products have led to significant therapeutic advances and commercial success in recent years. Menthol is a naturally occurring cyclic menthol alcohol found in a variety of plants, especially members of the mint family such as peppermint and spearmint. It is a common ingredient in a wide range of confectionery, chewing gum, and oral care products. Interestingly, menthol also has high medicinal value due to its analgesic, anti-inflammatory, and anti-cancer effects.

In a recent study, a team of scientists led by Professor Gen-Ichiro Arimura from the Department of Bioscience and Technology, Tokyo University of Science, Japan, developed and studied menthyl esters of valine (MV) and isoleucine (MI), which are derivatives of menthol obtained by replacing its hydroxyl group with valine and isoleucine, respectively.

Their results were published in the journal Immunology.

Sharing the motivation behind the current work, Professor Arimura said: “Functional components of plants that contribute to human health have always interested me. The discovery of new molecules from natural materials inspired our research group to develop these amino acid derivatives of menthol.”

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 studies on cell lines. Finally, they conducted experiments in mice to study the effects of these compounds in induced disease conditions. The exceptional anti-inflammatory profiles of MV and MI were determined by assessing the transcription levels of tumor necrosis factor-α (Tnf) in stimulated macrophage cells.

Surprisingly, 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.

The researchers went further and studied the mechanism of action of menthyl esters. They found that the liver X receptor (LXR), an intracellular nuclear receptor, plays an important role in the anti-inflammatory effects, and this is independent of the cold-sensitive transient receptor TRPM8, which primarily detects menthol.

Delving deeper into the LXR-dependent activation of MV and MI, they found that the Scd1 gene, central to lipid metabolism, was activated by LXR. Moreover, in mice with induced intestinal colitis, the anti-inflammatory effects were further confirmed by the suppression of the transcriptional levels of Tnf and Il6 genes by MV or MI in a LXR-dependent manner.

Motivated by the discovery of the intracellular mechanics of LXR-SCD1, Professor Arimura and his team hypothesized that menthyl esters have anti-obesity properties. They found that these esters inhibited adipogenesis, the accumulation of fat, especially at the mitotic clonic expansion stage in 3T3-L1 adipocyte cells. In animal studies, diet-induced obesity in mice was mitigated and adipogenesis was suppressed.

Menthyl esters have unique advantages over other anti-inflammatory or anti-obesity compounds currently being researched or used. Their specific mechanisms of action, which 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 be useful for certain populations, such as those with chronic inflammatory diseases, metabolic syndrome, or obesity-related complications.

“While this study focused on their functions and mechanisms of action in inflammation- and obesity-related disease models, we expect that these compounds will also be effective against a wide range of metabolic syndrome-related diseases such as diabetes and hypertension, as well as allergic symptoms,” Professor Arimura optimistically noted.

In conclusion, this study highlights the importance and value of multifunctional molecules derived from natural substances. Future studies of these new and superior menthyl esters may lead to the development of therapeutic compounds to combat the growing health problems associated with obesity and inflammatory conditions.