Researchers Have Discovered a Molecule that Reduces Fat Mass in Mice-BAM15

Non-alcoholic steatohepatitis (NASH), also known as metabolic steatohepatitis, is a common chronic liver disease closely related to metabolic disorders such as obesity, insulin resistance, type II diabetes, and hyperlipidemia. NASH animal model is an important vehicle for studying non-alcoholic steatohepatitis. NASH is manifested by severe liver fat accumulation and inflammation, often accompanied by fibrosis and metabolic disorders, and eventually leads to more severe liver cirrhosis and liver cancer, which is more common in middle-aged, especially overweight and obese individuals. Recently, Webster Santos, a professor of chemistry at Virginia Tech, USA, and his colleagues discovered a small molecule that can reduce the amount of fat in mice without affecting food intake and muscle mass or increasing body temperature. It is expected to explore drugs for the treatment of non-alcoholic steatohepatitis.

ATP, adenosine triphosphate is the direct source of energy for various life activities, and mitochondria are the main places where ATP is produced. In order to produce ATP, it is necessary to “burn” nutrients and build a proton power (PMF) in the mitochondria. PMF is produced by a proton gradient. In the proton gradient, the proton concentration outside the inner membrane is higher, while the proton concentration in the matrix or membrane space is lower. Whenever protons pass through an enzyme called ATP synthase, the cell produces ATP, which is embedded in the cell membrane. Therefore, nutrient oxidation or nutrient combustion is coupled with ATP synthesis.

Santos said, “Any substance that lowers PMF may increase respiration. Mitochondrial uncoupling agents are small molecules that enter the mitochondria and help cells breathe more. Mitochondrial uncoupling agents effectively change the metabolism in the cell. It allows us to burn more calories without doing any exercise.”

BAM15 is a new type of mitochondrial proton carrier uncoupling agent. Its working principle is to reduce the efficiency of mitochondria. Mitochondria are the power source of cells. As a result, mitochondria burn more energy. Mitochondrial uncoupling agents bypass ATP synthase to transport protons into the matrix, and ATP synthase releases proton power. In order to reconstruct the gradient, protons must be derived from the mitochondrial matrix. As a result, the cells begin to burn energy at a higher level than necessary. The incidence of NASH is rising rapidly, which is related to the rising incidence of obesity. Studies have found that 20%-30% of patients with diabetes and obesity will cause NASH, and 69%-87% will have NAFLD.

NASH animal models can be successfully replicated through a high-cholesterol diet. MCD and HFD are two common feeds for inducing NASH. Researchers can choose the appropriate method according to the modeling characteristics, cycle, and animal type of each method. Medicilon has rich experience and effective animal models in the evaluation of new NASH drugs, including golden hamsters induced by high-fat feeding, rat models, and mouse models induced by MCD feed. And it has effective evaluation models for NAFLD fibrosis stage, including: TAA-induced liver fibrosis (rat), compound factor method-induced rat liver fibrosis model (rat), ConA-induced mouse liver fibrosis (small Rats), pig serum-induced immune rat liver fibrosis model (rats), etc.

  Understanding that these molecules can change the metabolism of cells, researchers want to make sure that the drug has achieved the desired goal, and most importantly, it is safe. Through a series of studies on mouse models, the researchers found that BAM15 is not toxic even at high doses, nor does it affect the brain’s satiety center. In the research of the researchers in the MAM15 mouse model, these mice ate as much food as the mice in the control group, but their fat mass was indeed reduced.

Another side effect of mitochondrial uncoupling agents earlier was an increase in body temperature. Researchers used rectal probes to measure the body temperature of mice fed BAM15. They found that the body temperature of the mice was the same as before feeding. But there is a question about the half-life of BAM15. In the mouse model, the half-life of the drug, that is, the time the drug maintains its efficacy, is relatively short. For human oral administration, the optimal half-life is much longer.

  Even though BAM15 has great potential in mouse models, this drug does not mean that it will be successful in humans, at least not the exact same molecule.

At present, researchers are basically looking for roughly the same type of molecule, but it needs to stay in the body for a longer period of time to have an effect. Researchers have made hundreds of molecules related to this by adjusting the chemical structure of the compound.

  The ultimate goal of the Santos laboratory is to transfer the anti-fat treatment in animal models to the treatment of non-alcoholic fatty liver in humans. The laboratory has used better compounds in animal non-alcoholic fatty liver models. These compounds have been proven to be effective against non-alcoholic fatty liver in mice. We expect these compounds to eventually be put into clinical use.