Scientists have unveiled a new weight-loss pill that works directly within the gut, offering a fundamentally different approach to weight management than currently available injectable medications. The pill, developed by researchers at Nanyang Technological University in Singapore, aims to reduce the amount of dietary fat absorbed by the body without impacting appetite or brain chemistry.
Unlike popular medications such as Ozempic and Wegovy, which primarily function by suppressing appetite and regulating blood sugar, this new compound acts locally within the intestines. It specifically blocks a receptor on intestinal cells responsible for transporting fats into the body, thereby reducing the amount of fat transferred from the gut to the liver. The compound promotes the growth of beneficial gut bacteria that produce short-chain fatty acids, which have been shown to reduce inflammation and strengthen the intestinal barrier.
This targeted approach may offer an alternative for individuals who struggle with or are ineligible for existing weight-loss treatments, potentially avoiding the gastrointestinal side effects – diarrhea, constipation, or stomach paralysis – often associated with GLP-1 agonists.
In studies conducted on animal models, mice fed a high-fat diet and given the oral compound gained significantly less weight compared to untreated mice, and importantly, without exhibiting any toxic side effects or systemic exposure. This suggests a potentially safer profile than some existing medications.
However, a key consideration with current GLP-1 medications is the need for indefinite continuation, even after weight-loss goals are achieved. It remains unclear whether this new gut-based compound will require the same long-term commitment.
Dr. Andrew Tan, a metabolic disorders expert and co-creator of the compound, explained, “Our findings suggest that applying a controlled brake on fat absorption in the gut can help reduce the amount of fat reaching the liver, particularly during periods of high-fat intake or for people who are unable to exercise.”
The development of alternative weight-loss strategies is particularly urgent given the scale of the obesity epidemic. With over 40 percent of Americans classified as obese, obesity has become a major public health concern, contributing to increases in type 2 diabetes, fatty liver disease, and heart disease.
Despite widespread awareness of healthy dietary guidelines, modern food environments, characterized by high levels of saturated fats and refined sugars, continue to promote caloric excess. Data indicates that Americans obtain roughly half of their daily calories from ultra-processed foods.
The researchers began by creating a library of 52 artificial compounds designed to mimic naturally occurring fats produced by the body. They then modified these compounds to enhance their stability in the presence of stomach acid during digestion. These candidates were tested on human liver and colon cells, using fluorescent dyes to visualize the interaction between fat molecules and receptors on intestinal cells.
The results showed that the best-performing compounds effectively blocked fat from entering intestinal cells, without interfering with sugar metabolism. Three compounds – 12-TAASA, 12-SAASA, and 12-HDTZSA – demonstrated promising results, remaining largely intact even after simulated exposure to stomach acid.
Subsequent animal studies involved feeding mice a high-fat, high-calorie diet. Some mice received daily oral doses of the experimental compounds, while others received injections of semaglutide. Analysis of blood and stool samples revealed that the compounds remained primarily within the gut, with minimal systemic absorption.
After four weeks, mice receiving 12-TAASA gained significantly less weight than untreated mice, despite consuming the same diet. Their livers were also lighter, less fatty, and showed reduced scarring. Glucose tolerance tests revealed performance comparable to that of mice receiving semaglutide injections.
The gut microbiome also underwent positive changes. Levels of harmful, inflammation-linked bacteria, such as Romboutsia, decreased, while beneficial strains like Blautia and Roseburia flourished. Blood levels of acetate, propionate, and butyrate – metabolites known to improve insulin response and reduce inflammation – increased significantly.
Fluorescent fat tracking provided further evidence of the compound’s effectiveness. In untreated mice, a glowing lipid shake resulted in visible fat accumulation in the portal veins and liver. However, in mice treated with 12-TAASA, the signal was significantly fainter and delayed, indicating that less fat escaped the gut and reached the liver.
If these findings translate to humans in future clinical trials, the impact could be substantial. Many existing weight-loss drugs work by altering brain chemistry, suppressing appetite, or slowing stomach emptying. While effective, these mechanisms can also lead to side effects such as nausea, muscle loss, and vomiting.
The experimental compound, by not directly affecting brain chemistry, did not exhibit these side effects in animal trials. This could make it particularly appealing to the millions of Americans seeking weight management solutions but wishing to avoid needles or gastrointestinal symptoms.
For patients with fatty liver disease, the benefits could be even more significant. Reducing fat delivery to the liver could potentially reverse the condition, mitigating inflammation, scarring, and the increased risk of liver failure or cancer. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is increasingly recognized as a driver of systemic health risks.
While the results are promising, it’s important to note that the research is currently limited to animal models. Human biology differs significantly from that of mice, and the compound’s efficacy and safety in humans remain to be determined. The NTU team has partnered with a biotechnology firm to advance the technology to human trials, a process that will require substantial investment and regulatory approval. Even under optimal conditions, This proves likely to take several years before the new pill becomes available to the public.
