Breakthrough new drug stops fat buildup and reverses obesity in clinical trial

Obesity remains one of the greatest health challenges worldwide, leading to diabetes, heart disease, and increased healthcare costs. Lifestyle changes and improved diets are critical but often insufficient once obesity has taken hold. New drugs, such as GLP-1 agonists like semaglutide, have emerged as effective treatments.

However, alternatives or complementary treatments could further improve results and reduce side effects. Researchers may now have found such an alternative in a newly developed compound named SANA, a derivative of the common pain-reliever salicylate, best known as aspirin's ancestor.

Scientists originally designed SANA, short for 5-(2-nitroethenyl)salicylic acid, to fight inflammation, a key factor in obesity-related illnesses. Instead, early experiments revealed something unexpected: SANA prevented mice from gaining weight, even when eating high-fat diets.

Animals given the compound alongside their food did not become obese. Those already obese shed significant weight within weeks, reducing fat in the liver and improving insulin sensitivity.

Unlike most weight-loss medications, SANA works uniquely by activating thermogenesis, the body's process of generating heat to burn calories. Normally, thermogenesis involves a protein called UCP1 within mitochondria, the energy factories in cells. However, SANA stimulates thermogenesis without UCP1, using a molecule called creatine instead.

"We conducted tests with UCP1-deficient mice and proved that SANA activates thermogenesis even without this protein and under normal temperature conditions," said William Festuccia, professor at the Biomedical Sciences Institute at the University of São Paulo.

This distinct action means SANA specifically targets fat tissue, reducing the risk of overheating and cardiovascular stress seen in older thermogenic drugs. The effect on body temperature is minor, ensuring safety while effectively burning calories.

A rigorous phase 1 clinical trial involving human volunteers tested SANA's safety and potential benefits. Conducted in two parts, the study evaluated different doses: a single dose ranging from 200 to 800 mg and multiple doses from 200 to 400 mg daily for 15 days. Healthy, overweight, or obese volunteers participated.

The results were encouraging. Participants tolerated SANA well, experiencing no severe side effects. More importantly, those taking the highest dose showed improved insulin resistance and weight loss within just two weeks.

"The observed effects were significantly stronger than what we’ve seen with salicylate alone," noted Escande.

SANA could become the first in a new class of obesity drugs, potentially complementing existing treatments like GLP-1 agonists. Because it uses a novel mechanism, it can combine with drugs like semaglutide, enhancing overall weight-loss effectiveness.

"When food intake is reduced, metabolism tends to slow down. Combining a molecule that suppresses appetite with another boosting caloric expenditure could prevent the plateau effect often seen in dieting," explained Marcelo Mori from the Institute of Biology at the State University of Campinas.

Moreover, unlike GLP-1 drugs that sometimes cause muscle loss, particularly concerning for elderly users, SANA specifically burns fat without affecting muscle mass. "That’s why having alternatives is important," Mori added.

SANA's beneficial effects stem from the nitroalkene chemical group attached to salicylate. This group triggers several beneficial pathways related to energy production in cells.

Scientists initially explored nitroalkenes using vitamin E structures, finding improvements in inflammation, glucose intolerance, and heart disease during obesity. They then tested the nitroalkene with salicylate, yielding remarkable, unexpected results.

Studies also revealed SANA increases mitochondrial respiration—the cell's way of burning calories efficiently—and enhances the creatine cycle in adipose (fat) tissue. Creatine cycles between forms, consuming energy and releasing heat. This cycle is critical to SANA’s success, as proven when mice lacking a key enzyme in this process failed to benefit from the drug.

"We observed weight loss and improved blood sugar levels in obese volunteers who participated in the phase 1 clinical trial," explained Carlos Escande, a researcher at the Pasteur Institute in Montevideo, Uruguay. But he cautioned, "this result isn’t conclusive because it was a small group, and the objective was to assess whether the compound is safe and well-tolerated."

Researchers now aim to move into phase 2 clinical trials, focusing on proving SANA’s effectiveness in larger human populations. If successful, SANA might represent a significant advancement in obesity treatment, providing millions worldwide with a safer, more efficient way to manage weight and metabolic health.

"We intend to start phase 2 of the study later this year, designed specifically to test effectiveness," Escande emphasized.

By harnessing the body's natural heat-generating processes in a targeted and safe manner, SANA could reshape obesity treatment, offering new hope to those struggling with this widespread, difficult-to-treat condition.

Note: The article above provided above by The Brighter Side of News.

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