Wonderdrug derived from menthol could fuel weight loss, reduce inflammation

TOKYO — Weight loss treatments could soon get a minty-fresh new weapon in the fight against obesity. Researchers from Tokyo University of Science have developed novel derivatives of menthol, the well-known compound that gives mint its refreshing properties, into a potential treatment for losing weight and relieving inflammation. The findings, published in the journal Immunology, offer new hope in the battle against these widespread health issues.

Menthol has long been recognized for its cooling sensation and various therapeutic uses, from pain relief to reducing inflammation. However, the Tokyo University of Science team, led by Prof. Gen-ichiro Arimura, wanted to see if they could enhance menthol’s beneficial properties by chemically modifying it. They focused on combining menthol with amino acids, the building blocks of proteins, to create what are known as menthyl esters.

The researchers synthesized several different menthyl esters and tested their effects on inflammation in immune cells called macrophages. Macrophages play a crucial role in inflammation – they are like the body’s first responders, rushing to sites of infection or injury. However, when macrophages become overactive, they can contribute to chronic inflammation, which is linked to various health problems.

Excitingly, the team found that two specific menthyl esters, abbreviated as MV and MI, had potent anti-inflammatory effects in the macrophages. These compounds significantly reduced the production of inflammatory molecules like tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). In fact, MV and MI were even more effective at quelling inflammation than menthol itself.

“The functional components of plants that contribute to human health have always intrigued me. Discovering new molecules from natural materials inspired our research team to develop these amino acid derivatives of menthol,” says Prof. Arimura in a university release.

The menthyl esters of valine (MV) and isoleucine (MI) are multi-faceted molecules with enhanced anti-inflammatory and anti-obesity activities.

So, how exactly do these menthyl esters work their anti-inflammatory magic? The researchers discovered that unlike menthol, which primarily acts through a cold-sensing protein on the cell surface called TRPM8, MV and MI use a different mechanism. These compounds can easily enter cells and interact with a protein called the liver X receptor (LXR).

LXR is like a master switch for regulating inflammation and lipid metabolism in cells. When activated, it can turn down inflammatory responses. The menthyl esters MV and MI were found to bind to and activate LXR, working synergistically with it to reduce inflammation. Interestingly, how MV and MI activate LXR differs from how other known LXR-activating compounds work. This suggests that the menthyl esters uniquely interact with LXR.

In addition to their anti-inflammatory effects, the researchers found that MV and MI also had impressive anti-obesity properties. In experiments with cultured fat cells called adipocytes, the menthyl esters inhibited the cells’ ability to accumulate fat. They did this by interfering with a process called adipogenesis, where immature fat cells develop into mature fat-storing cells. Notably, MV and MI affected a specific stage of adipogenesis called mitotic clonal expansion, independently of LXR.

To test if these exciting cellular findings would translate to whole-body effects, the team gave mice either a high-fat diet to induce obesity or a chemical called dextran sulfate sodium (DSS) to induce colitis, a form of gut inflammation. Mice treated orally with MV or MI showed reduced weight gain, smaller fat deposits, and less severe colitis than untreated mice. This demonstrates that menthyl esters can combat obesity and inflammation in a living organism, not just in cells in a dish.

The implications of this study are far-reaching. Chronic inflammation and obesity are significant public health burdens worldwide. Obesity is a risk factor for many life-threatening conditions like diabetes, heart disease, and certain cancers. Meanwhile, unchecked inflammation contributes to painful autoimmune disorders like rheumatoid arthritis and inflammatory bowel disease. Having new therapeutic options to tackle these issues could improve the quality of life for millions.

“Although this study focused on their functions and mechanisms of action in diseases modeled after inflammation and obesity, we expect that these compounds will also be effective against a wide range of lifestyle-related diseases caused by metabolic syndrome, such as diabetes and hypertension, as well as allergic symptoms,” Prof. Arimura concludes.

While more research is necessary before MV and MI can be developed into medications for human use, their multi-pronged beneficial effects make them exciting candidates. The fact that they are derived from a natural, familiar compound like menthol could facilitate their path to the clinic. Additionally, unraveling their unique modes of action could provide new insights into the fundamental cellular processes underlying inflammation and obesity. With further development, MV and MI may one day help turn the tide against these widespread health challenges.

StudyFinds Editor Chris Melore contributed to this report.

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