Innovative inhibitors promise to fight obesity and heart disease

Obesity is a worldwide problem and one of the main factors causing heart disease. A recent study found that mice lacking the cytochrome P450 8B1 gene were resistant to weight gain and improved glucose tolerance when fed a high-fat diet. Therefore, inhibition of P450 8B1 is a target for the treatment of obesity-related metabolic disorders.
According to the World Health Organization, 1.9 billion adults worldwide were overweight in 2016 and 650 million were classified as obese. Heart disease kills 1 in 4 people in the United States, and obesity is a major factor. According to a recent report from the SAN Antonio Metropolitan Health Region, 71 percent of adults there are overweight or obese.
An interdisciplinary team of researchers at the University of Texas at SAN Antonio (UTSA) has successfully developed an innovative inhibitor that shows promise in fighting obesity and potentially preventing heart disease. Francis Yoshimoto, assistant professor in the Department of Chemistry in the UTSA School of Science, led a team to develop an anti-obesity drug that blocks the effects of cytochrome P450 8B1, an enzyme involved in cholesterol absorption and obesity.
Yoshimoto teamed up with Eunhee Chung, an associate professor in the Department of Kinesiology at UTSA’s School of Health, Community and Policy, to test the new drug. After designing the synthesis, Yoshimoto sends test samples to an NIH-funded lab in Chung, where she and her research team are studying the effects of bioactive compounds (small amounts of chemicals found in plants and certain foods) and how exercise can be used to treat obesity and related metabolic disorders.
Their findings were published in the February 2022 issue of the scientific journal Steroids, Entitled “A synthesis of A Rationally designed inhibitor of Cytochrome P450 8B1, A therapeutic target to treat obesity”. “Growing up, I dreamed of helping members of my family who are affected by diseases like obesity and heart disease,” Yoshimoto said. This dream is now becoming a reality because we have developed a small molecule that can be used to combat obesity, a problem that is seen in many families around the world.”
Chung added: “As an exercise physiologist, I really believe that exercise is the best medicine against NCDS. Unfortunately, the prevalence of obesity is on the rise with relatively low levels of exercise adherence. Based on promising data, I have high hopes for further testing of Dr. Yoshimoto’s inhibitor.”
UTSA’s drug has the potential to block the activity of P450 8B1, an enzyme in the body that produces cholic acid. This inhibition, in turn, reduces cholesterol absorption. This process could hold the key to treating obesity-related metabolic disorders and other obesity-related conditions, such as heart disease and diabetes.
The team’s study involved treating mice with an inhibitor drug for seven days. The result was a drop in glucose levels in their blood — even though they were fed a high-fat and high-sucrose diet — with no effect on their weight. The results demonstrate that P450 8B1 inhibitors can lead to a healthier metabolic profile, with the potential to lead to the development of a therapeutic strategy for obesity-related insulin resistance.
Yoshimoto and Chung’s work represents UTSA’s mission to develop solutions to the complex challenges of improving the health and well-being of society. Creating an effective obesity prevention drug could improve the quality of life around the world.
“These results show how our research in synthetic chemistry can significantly contribute to the well-being of society by treating obesity and heart disease,” Yoshimoto said.