New nanoparticle therapy targets fat absorption to fight obesity

Researchers have unveiled a new approach to combating obesity by targeting fat absorption in the small intestine. The cutting-edge nanoparticle system, designed to deliver therapeutic molecules directly into the digestive tract, has shown significant potential to prevent diet-induced obesity. The work is published in the journal Advanced science.

Presented during UEG Week 2024, the study focuses on an enzyme called Sterol O-acyltransferase 2 (SOAT2), which plays a critical role in fat absorption in the small intestine. By inhibiting this enzyme in the small intestine, the study offers a promising therapeutic approach to reduce fat absorption and potentially prevent obesity.

Despite extensive research into fat metabolism, effective inhibitors of intestinal fatty acid absorption have remained elusive until now. “For years, researchers have studied fat metabolism, but it has been difficult to find an effective way to block fat absorption,” explained lead researcher Dr. Wentao Shao. “While most strategies focus on reducing dietary fat intake, our approach directly targets the body’s fat absorption process.”

The research team developed an innovative delivery system using nanoparticles: a tiny capsule made of a polymer core, covered with a protective shell.

The system was designed to efficiently transport small interfering RNA (siRNA) to the small intestine, where they can reduce SOAT2 expression, thereby inhibiting fat absorption. In mouse models, animals treated with nanoparticle therapy absorbed less fat and avoided obesity, even on a high-fat diet.

“This oral treatment offers several benefits,” said Dr. Shao. “It is non-invasive, has low toxicity and has high potential to improve patient compliance compared to current obesity treatments, which are often invasive or difficult to maintain. This makes it a promising alternative. “

The study also uncovered the underlying mechanism by which SOAT2 regulates fat absorption. Inhibition of SOAT2 in the small intestine triggers the degradation of CD36, a protein responsible for fat transport. This process involves both cellular stress and the recruitment of the E3 ligase RNF5, an enzyme that enhances CD36 degradation.

Previous studies showed that blocking hepatic SOAT2 led to fat accumulation in the liver, whereas this gut-specific approach circumvented this risk, providing a safer and more targeted treatment of obesity.

Professor Zhaoyan Jiang, study supervisor, explained: “One of the most exciting aspects of this therapy is its ability to target fat absorption in the intestines without affecting the liver. This is important because previous studies have shown that blocking SOAT2 in the liver can lead to fat accumulation there – a risk our treatment avoids by focusing solely on intestinal SOAT2. »

Moving forward, the research team plans to test the nanoparticle system in larger animal models to confirm its effectiveness and safety for potential use in humans.

“We believe this nanoparticle system represents a breakthrough in obesity management, offering a new solution that addresses both fat metabolism and diet-related weight gain, potentially paving the way to a new era of more effective treatments,” concluded Professor Jiang.