An article published in the journal Nature Metabolism describes an experimental drug that activates fat cells to produce heat via thermogenesis, thereby promoting weight loss. In animal testing, it has been shown to prevent fat accumulation on a high-fat diet and to reduce existing obesity and insulin resistance.
Preliminary results suggest that the substance is safe and may have a beneficial effect on human metabolism.
“In obese volunteers in the first phase of the clinical trial, we observed a loss of body weight and an improvement in blood sugar levels. However, these results are not conclusive because the study included a small number of participants and focused primarily on the drug’s safety profile. We plan to start the second phase of the study later this year, which will be focused on evaluating the effectiveness of the treatment of obesity”, said Carlos Escand, researcher and coordinator of the study at the Pasteur Institute Montevideo.
The experimental drug, known as SANA (short for “salicylate-based nitroalkene”), is a derivative of salicylate, a chemical compound with analgesic and anti-inflammatory properties that occurs naturally in plants and is used in the production of drugs such as aspirin.
According to Carlos Escando, his team sought to develop an anti-inflammatory drug and tested various chemical modifications of the salicylate molecule.
“We wanted the precursor to be as safe as possible. Salicylate is a drug with a long history, and its derivatives are used every day. However, we noticed that a molecule that should protect against inflammation actually protects against diet-induced obesity,” explains the researcher.
The drug’s effect was tested in two animal models. In the first model, SANA was given to mice on a high-fat diet, completely preventing body weight gain, whereas animals in the control group gained 40%-50% of their body weight during the same period.
In the second model, the therapy was started in animals with already established obesity, and after 3 weeks, the mice lost about 20% of their body weight.
A drop in blood sugar levels, improved insulin sensitivity, and a reduction in liver fat (hepatic steatosis) were also observed, for which there is still no effective pharmacological therapy.
First in Class
The next step of research was to study the mechanism of action of the substance. Nine Brazilian researchers worked on this part of the project: 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. FAPESP financially supported this phase of the study through three projects.
The results of the experiments indicate that SANA has a targeted effect on fat tissue, activating thermogenesis through an unconventional mechanism. Therefore, it can be considered a representative of a completely new class of anti-obesity drugs. The substance does not affect the central nervous system, digestive tract, or appetite.
The authors explain that in standard thermogenesis, energy is released mediated by the protein UCP-1, which is found in energy-producing mitochondria. UPC1 is activated in certain situations, such as exposure to cold. It interferes with the synthesis of ATP (adenosine triphosphate), due to which the energy produced by cellular respiration turns into heat.
SANA, however, works differently: the drug encourages adipocytes to use creatine, a compound made of three amino acids (arginine, glycine, and methionine) as an energy source for heat production, without involving the UCP1 protein.
“We tested the SANA drug in mice that do not produce the UCP1 protein and proved that the substance can trigger thermogenesis in these animals, even in conditions without exposure to cold,” says William Festuccia, a professor at the Institute of Biomedical Sciences of the University of Sao Paulo.
He noted that the drug’s effect on body temperature is minimal and does not pose a health risk. “Older thermogenic agents, such as dinitrophenol, act on the mitochondria of the whole body, leading to a significant increase in body temperature and the load on the cardiovascular system.
In these conditions, blood pressure must rise to disperse the heat around the periphery. SANA, however, acts exclusively on the mitochondria of adipose tissue,” explains Festuccia.
Experiments coordinated by Marcello Mori at the Institute of Biology of UNICAMP (State University of Campinas) showed that SANA activates enzymes that participate in the so-called “creatine senseless cycle”. In this thermogenic process, creatine and phosphocreatine are continuously converted, consuming ATP and releasing energy as heat.
“SANA is a small molecule and works by a different mechanism, which allows it to be used in combination with other drugs used in the treatment of obesity, such as GLP-1 analogs (Semaglutide and similar),” points out Marcelo Mori.
“When we reduce food intake, the metabolism naturally slows. To avoid the plateau effect, it is useful to combine a molecule that suppresses appetite with one that increases calorie consumption.”
Mori notes that although GLP-1 analogs are effective for weight loss, they often reduce lean body mass, which can be a problem in older patients. “That’s why it’s crucial to use alternative options,” he concludes.
