Fresh Mint, Slimmer You: Scientists Discover Fat-Fighting Molecules
Fat-fighting molecules
Scientists have successfully synthesized intricate menthyl esters and elucidated the underlying mechanism of their interaction with the liver X receptor (LXR).
The development of menthyl esters with pronounced anti-inflammatory and anti-obesity properties by researchers holds promise for novel treatments targeting chronic inflammatory diseases and metabolic disorders.
Recent therapeutic breakthroughs and commercial milestones often stem from modified derivatives of natural compounds. Menthol, a naturally occurring cyclic monoterpene alcohol, is abundant in various plants, particularly in the mint family, such as peppermint and spearmint.
It finds widespread use in confectionery, chewing gum, and oral care products. Beyond its commercial applications, menthol exhibits significant medicinal benefits, including analgesic, anti-inflammatory, and anti-cancer properties.
In a recent study led by Professor Gen-ichiro Arimura from the Department of Biological Science and Technology at Tokyo University of Science, Japan, researchers developed and scrutinized menthyl esters of valine (MV) and isoleucine (MI).
These esters are synthesized by substituting menthol’s hydroxyl group with valine and isoleucine, respectively.
Their findings were published in the journal Immunology.
Reflecting on the motivation behind this work, Prof. Arimura remarked, “The health-enhancing components of plants have always captivated my interest.
The discovery of new molecules from natural sources fueled our research to develop these amino acid derivatives of menthol.”
Anti-Inflammatory Potency of Menthyl Esters
The researchers began by synthesizing menthyl esters from six amino acids, each with less-reactive side chains.
They then evaluated these esters’ properties through in vitro studies on cell lines, followed by experiments in mice to assess their effects under induced disease conditions.
The exceptional anti-inflammatory profiles of MV and MI were determined by measuring the transcript levels of tumor necrosis factor-α (Tnf) in activated macrophage cells.
Notably, both MV and MI surpassed menthol in the anti-inflammatory assays. RNA sequencing further revealed that 18 genes associated with inflammatory and immune responses were effectively downregulated.
Encouraged by their results, the researchers delved deeper into the mechanism of action of the menthyl esters.
They identified that the liver X receptor (LXR), an intracellular nuclear receptor, plays a crucial role in the anti-inflammatory effects, independent of the cold-sensitive transient receptor TRPM8, which primarily detects menthol.
Further exploration into the LXR-dependent activation of MV and MI revealed that the Scd1 gene, essential for lipid metabolism, was upregulated by LXR.
Additionally, in mice with induced intestinal colitis, the anti-inflammatory effects were corroborated by the reduced transcript levels of Tnf and Il6 genes via MV or MI, in an LXR-dependent manner.
Potential Anti-Obesity Benefits
Driven by the revelation of the LXR-SCD1 intracellular mechanism, Prof. Arimura and his team postulated that menthyl esters possess anti-obesity properties.
They observed that these esters inhibited adipogenesis—fat accumulation—specifically at the mitotic clonal expansion stage in 3T3-L1 adipocyte cells. In animal studies, diet-induced obesity in mice was mitigated, and adipogenesis was suppressed.
Menthyl esters offer distinct advantages over other anti-inflammatory or anti-obesity compounds currently under research or in use.
Their specific mechanisms, contributing to both anti-inflammatory and anti-obesity effects, distinguish them from other compounds and may make them particularly effective in addressing both inflammatory and metabolic disorders.
They could be particularly beneficial for individuals with chronic inflammatory conditions, metabolic syndrome, or obesity-related complications.
“While this study concentrated on the compounds’ functions and mechanisms in disease models related to inflammation and obesity, we anticipate that these compounds will also be effective against a broad spectrum of lifestyle-related diseases caused by metabolic syndrome, such as diabetes and hypertension, as well as allergic reactions,” says Prof. Arimura with optimism.
In conclusion, this study highlights the significance and potential of multi-functional molecules derived from naturally occurring substances.
Future research on these innovative and superior menthyl esters may yield therapeutic compounds capable of addressing the growing health challenges posed by obesity and inflammatory conditions.
Reference
“The powerful potential of amino acid menthyl esters for anti-inflammatory and anti-obesity therapies” by Seidai Takasawa, Kosuke Kimura, Masato Miyanaga, Takuya Uemura, Masakazu Hachisu, Shinichi Miyagawa, Abdelaziz Ramadan, Satoru Sukegawa, Masaki Kobayashi, Seisuke Kimura, Kenji Matsui, Mitsunori Shiroishi, Kaori Terashita, Chiharu Nishiyama, Takuya Yashiro, Kazuki Nagata, Yoshikazu Higami, and Gen-ichiro Arimura, 08 May 2024, Immunology.
This research was partially funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI (20H02951 and 24K01723) and Tokyo University of Science Research Grants awarded to Gen-ichiro Arimura.
Fat-fighting molecules
