New fat-blocking nanotherapy tackles diet-caused obesity at the source

A new oral nanotherapy works directly on the small intestine, reducing its ability to absorb fat from the food we eat, according to a new study. While the therapy is at the early stages, if it proves effective in humans, it has huge potential as a treatment for diet-related obesity.

In 2022, 43% of adults worldwide were overweight. Of these, 16% were living with obesity. As many would already know, being overweight and obese increases the risk of type 2 diabetes, heart disease, and certain cancers.

Despite years of study resulting in an understanding of how fat is metabolized in the body, identifying an effective way of inhibiting its absorption in the intestine has remained out of reach. However, a new study may have the answer: oral nanoparticles that work directly on the small intestine to reduce the production of an enzyme responsible for fat absorption.

“For years, researchers have studied fat metabolism, but finding an effective way to block fat absorption has been difficult,” said Dr Wentao Shao, from the School of Medicine at Tongji University, Shanghai, and one of the study’s authors. “While most strategies focus on reducing dietary fat intake, our approach targets the body’s fat absorption process directly.”

The enzyme in question is Sterol O-acyltransferase 2 (SOAT2), which is encoded by the SOAT2 gene. Uniquely present in liver cells (hepatocytes) and absorptive cells in the intestinal lining (enterocytes), SOAT2 has been studied extensively in relation to its role in the development of atherosclerosis or plaque buildup in the arteries.

The researchers used nanoparticles containing small interfering RNAs (siRNAs) that, when swallowed, are delivered to the small intestine. (siRNAs are renowned for regulating gene expression.) There, they reduced the expression of SOAT2 by enterocytes and, therefore, inhibited fat absorption. When the nanotherapy was tested on mice, even mice fed a high-fat diet absorbed less fat and avoided obesity.

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

The researchers were also able to identify the mechanism underlying the regulation of fat absorption by SOAT2. Inhibiting SOAT2 in the small intestine triggers the degradation of a protein responsible for transporting fat, CD36. The process triggers cellular stress, which causes the recruitment of an enzyme called E3 ligase RNF3, which enhances CD36 degradation.

Previous studies have found that blocking SOAT2 in hepatocytes leads to liver fat accumulation. In the present study, the researchers’ intestine-specific approach avoided that risk.

“One of the most exciting aspects of this therapy is its ability to target fat absorption in the intestines without affecting the liver,” said Professor Zhaoyan Jiang, also from Tongji University’s School of Medicine and the study’s co-corresponding author. “This is important because previous studies showed that blocking SOAT2 in the liver can lead to fat buildup there – a risk our treatment avoids by focusing only on intestinal SOAT2.”

The researchers will continue to test the effectiveness and safety of the nanotherapy in larger animal models before looking to test it in humans. If successful, the therapy has great potential.

“We believe that this nanoparticle system represents a breakthrough in obesity management, offering a new solution that tackles both fat metabolism and diet-related weight gain, potentially ushering in a new era of more effective treatments,” Jiang said.

The study was presented at United European Gastroenterology (UEG) Week 2024, billed as “The best gastroenterology congress in the world,” and published in the journal Advanced Science.

Source: United European Gastroenterology (UEG)