An article published in the journal Nature Metabolism presents an experimental drug that stimulates adipose tissue cells to produce heat through a process known as thermogenesis, thereby promoting weight loss. In animal tests, the compound prevented fat accumulation in response to a high-fat diet, treated existing obesity, and reversed associated metabolic disorders, including insulin resistance. Preliminary results from clinical research indicate that the substance is safe and may have beneficial metabolic effects on humans.
"We observed weight loss and improved blood sugar levels in obese volunteers who participated in the phase 1 clinical trial. But 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. We intend to start phase 2 of the study later this year, which is designed to test its effectiveness in treating obesity," Carlos Escande, a researcher at the Pasteur Institute in Montevideo, Uruguay, and coordinator of the study, told Agência FAPESP.
The experimental drug, currently called SANA (short for "salicylate-based nitroalkene"), is a derivative of salicylate, a chemical compound with analgesic and anti-inflammatory properties found naturally in plants and used to make drugs such as aspirin (acetylsalicylic acid). According to Escande, his group initially sought to develop an anti-inflammatory drug. To this end, they tested several chemical modifications to the salicylate molecule.
"We wanted the precursor used to be as safe as possible. Salicylate is the drug that's been known the longest, and many people consume its derivatives daily. However, we observed that instead of protecting against inflammation, the molecule we synthesized protects against diet-induced obesity," says the researcher.
Two different models were used to test this effect in animals. In the first model, SANA was administered to mice alongside a high-fat diet, which prevented any weight gain. Meanwhile, the animals in the control group gained between 40% and 50% of their body weight over eight weeks. In the second model, treatment began after the animals were obese. After three weeks, the mice had lost 20% of their body mass. There was also a reduction in blood sugar, improved insulin sensitivity, and a decrease in fat accumulated in the liver (a condition known as hepatic steatosis for which there is still no effective pharmacological treatment).
First in class
The next step was to investigate the mechanism of action of the substance. Nine Brazilian researchers collaborated on this task: Marcelo Mori , Pedro Vieira and Larissa Menezes dos Reis from the State University of Campinas (UNICAMP); William Festuccia and Luiz Osório Leiria from the University of São Paulo (USP); and Juliana Camacho-Pereira, Marina Santo Chichierchio, Gabriele Barbosa, and Leonardo de Souza from the Federal University of Rio de Janeiro (UFRJ). This stage was supported by FAPESP through three projects ( 20/04159-8 , 21/08354-2 and 22/11234-1 ).
The experiments showed that SANA specifically targets adipose tissue, activating thermogenesis through an unconventional mechanism. It can therefore be considered the first in a new class of anti-obesity drugs. It does not affect the central nervous or digestive systems or appetite.
As the authors explain, thermogenesis is typically mediated by a protein called UCP1, which is found within mitochondria (the organelles that generate energy for cells). UCP1 is activated in certain situations, such as exposure to cold. It then interferes with the synthesis of ATP (adenosine triphosphate), the cellular fuel. This causes the energy generated by cellular respiration to dissipate as heat. However, this is not the case with SANA. The new drug causes adipocytes to use creatine, a compound formed by three amino acids (arginine, glycine, and methionine), as an energy source to produce heat without involving the UCP1 protein.
"We conducted tests with UCP1-deficient mice [genetically modified to not express the protein] and proved that SANA activates thermogenesis in these animals, even in the absence of UCP1 and under thermoneutral conditions, that is, without exposure to cold," says William Festuccia, a professor at the Biomedical Sciences Institute at USP.
According to the researcher, the observed impact on body temperature is small and does not pose a significant health risk. "Older thermogenic agents, such as dinitrophenol, have an effect on the mitochondria of the entire body, causing a large increase in temperature and overloading the cardiovascular system, which needs to increase blood pressure for blood to reach the periphery and dissipate heat. But in the case of SANA, there's only action on the mitochondria of adipose tissue," he explains.
In experiments coordinated by Marcelo Mori at the Institute of Biology at UNICAMP, it was confirmed that SANA acts on enzymes involved in the so-called "creatine futile cycle," a thermogenic mechanism in which the amino acid compound is repeatedly converted into phosphocreatine and back into creatine, consuming ATP and releasing energy as heat.
"The fact that it's a small molecule and acts through a totally different mechanism allows SANA to be combined with other substances already used in the treatment of obesity, such as GLP-1 analogs [semaglutide and similar]," says Mori. "When we reduce food intake, our body tends to slow down its metabolism. To avoid this plateau effect, it'd be interesting to combine a molecule that inhibits appetite with another that promotes caloric expenditure."
Mori adds that although GLP-1 analogs are effective in combating obesity and controlling blood sugar, they also tend to promote lean mass loss, which is particularly problematic for the elderly. "That's why it's important to have alternatives," he concludes.
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