Drugs To Burn Fat Not Affecting Food Intake Discovered
More than 40% of adults in the United States, and 13% of the global population are affected by obesity. A variety of interconnected diseases like diabetes, fatty liver disease, and cardiovascular disease comes with obesity and makes it most crucial and most difficult to treat.
Webster Santos, professor of chemistry and the Cliff and Agnes Lilly Faculty Fellow of Drug Discovery in the College of Science at Virginia Tech, said it is hard for people to lose weight and stay on a diet, so a drug could help out and be beneficial for all of society.
A small mitochondrial uncoupler, named BAM15 was recently identified by Santos and his colleagues, which decreases the body fat of mice without affecting muscle mass or food intake and without increasing body temperature.
BAM15 also decreases insulin resistance and has beneficial effects on inflammation and oxidative stress. This new discovery has the potential to treat and prevent diabetes, obesity, and especially a type of fatty liver disease called nonalcoholic steatohepatitis (NASH) characterized by fat accumulation and inflammation in the liver. The leading cause of liver transplants in the US in the next few years could be obesity.
Mitochondria is the organelle that generates energy in the form of ATP and is commonly referred to as the powerhouses of the cell. It powers biological processes and body movement and helo our body function properly.
Mitochondria burn nutrients and establish a proton motive force (PMF), in order to make ATP. There is a lower concentration of protons in the matrix, or the space within the inner membrane, and a higher concentration of protons outside of the inner membrane, which creates a proton gradient and generates the PMF.
As the protons pass through the ATP synthase enzyme in the membrane, ATP is generated by the cell. Therefore, nutrient burning and nutrient oxidation are coupled to ATP synthesis. Therefore, cellular respiration can be increased by decreasing the PMF.
Mitochondrial uncouplers are small molecules that help the cells to respire more. And as a result, the body burns more calories by changing the metabolism in the cell, even without doing any exercise.
These molecules bypass ATP synthase and transport protons into the matrix. This gets off the PMF. Then the protons need to be exported out of the mitochondrial matrix to reestablish the gradient. For that, the cell starts burning fuel more than usual.
However, the researchers wanted to be sure that this drug is safe and effective. They found that the BAM15 is not toxic even at higher doses. Mitochondrial uncouplers do not affect the satiety center of the brain as well, which tells the body is the person is full or hungry.
Many drugs that burn fat were discovered before, but they would tell the body to stop eating, and as a result, patients would rebound and eat more. But in this particular study, the mouse ate the same amount of food as the control group, but still lost the body fat mass. The previously discovered anti-fat drugs also increased body temperature. But in this case, they found no change in body temperature in the mice.
The only issue that arises in the case of BAM15 is its half-life. In the mouse model, the length of time that the drug is effective is relatively short. However, the optimal half-life is much longer for oral dosing in humans.
But this exact molecule might not be successful in humans. So the researchers are looking for roughly the same type of molecule that can stay in the body for a longer period and bring desired effects. They have already made several hundred molecules related to this by tweaking the chemical structure of the compound.
The Santos lab is aiming to change the anti-fat treatment from animal models to treatment for NASH in humans. The lab has used its better compounds proven to be effective as anti-NASH compounds in animal models of NASH.
Kyle Hoehn, an assistant professor of pharmacology from the University of Virginia, is also working alongside Santos, and he conducts animal studies. Hoehn and Santos had been working together for years, and they even founded a biotech company together.
Continuum Biosciences, co-founded by Hoehn and Santos in 2017, aims to improve the ways in which bodies burn fuel and fight back against our body’s ability to store excess nutrients as we age. Continuum Biosciences holds the license for the promising NASH treatment compounds, which are patented by Virginia Tech.
The mitochondrial uncouplers have a unique anti-oxygen effect that can minimize the accumulation of oxidative stress or relative oxygen species in our bodies that can cause aging and neurodegeneration. The researchers are hoping to use the mitochondrial uncouplers for more than just NASH and obesity.
Minimizing aging can reduce the risk of Parkinson’s disease and Alzheimer’s disease. All diseases associated with reactive oxygen species or inflammation can benefit from mitochondrial uncouplers.
Editor’s Note; Drugs to burn fat, Mitochondrial uncouplers to burn fat in mice.