Modern science has presented us with some experimental compounds that offer exciting possibilities when it comes to tackling obesity. Some trick the body into thinking that it has already had enough to eat, others manipulate the metabolic process so that the body burns off more fat than is actually necessary. Researchers have come across a new molecule that falls in with the latter category, reducing body fat in mice without changes to their diet.
Researchers from the Virginia Tech, the University of Virginia and Australia’s University of New South Wales teamed up to identify the molecule, which they say has the potential to overcome some of the drawbacks of other fat-fighting therapies that work by suppressing appetite and can result in patients eating more once the effects have worn off.
Called BAM15, the newly identified molecule is a type of “mitochondrial uncoupler” that instead works by targeting mitochondria, often described as the powerhouses of cells, and changing the way they consume energy and distribute it throughout the body.
The way it does this is by upping the concentration of protons within the inner membrane of the mitochondria. Normally, the mitochondria relies on a balance of protons on either side of this membrane, generating energy as they pass through a particular enzyme embedded inside the wall.
This is called proton motive force (PMF), and by increasing the proton numbers in the matrix while bypassing this key enzyme, the BAM15 molecule forces the cell to take corrective action. With excess protons inside, the cell responds by expelling them outside the membrane wall which, in fat-fighting terms, has the effect of burning fuel at higher levels than are actually needed.
“So anything that decreases the PMF has the potential to increase respiration," says Webster Santos, professor of chemistry at the Virginia Tech. “Mitochondrial uncouplers are small molecules that go to the mitochondria to help the cells respire more. Effectively, they change metabolism in the cell so that we burn more calories without doing any exercise.”
The researchers were able to demonstrate the effectiveness of the BAM15 molecule through a number of mouse studies, in which the rodents were administered the drug and exhibited weight loss, despite consuming the same diet as a control group. The team considers this proof that the molecule functions without affecting the satiety center in the brain that controls appetite, while it also appears to work without altering body temperature and was found to be non-toxic even in higher doses.
There is a lot of work to do to establish the effectiveness of BAM15 in humans, and there are certainly no guarantees. In addition to safety, one of the limitations the team is working to address is how long the dose remains effective for in the body, with its performance relatively short-lived in the mouse models. The researchers say they have already identified variations of the molecule that could offer a way forward.
“We are essentially looking for roughly the same type of molecule, but it needs to stay in the body for longer to have an effect,” says Santos. “We are tweaking the chemical structure of the compound. So far, we have made several hundred molecules related to this.”
If the technology can be adapted for use in humans, the researchers say it could be used to address a range of health problems, not just obesity and its related conditions like cardiovascular or fatty liver disease. The molecule was also shown to reduce inflammation and oxidative stress, which are related to the progression of degenerative diseases and aging.
“If you just minimize aging, you could minimize the risk of Alzheimer’s disease and Parkinson’s disease,” says Santos. “All of these reactive oxygen species-related or inflammation-related diseases could benefit from mitochondrial uncouplers. So, we could see this heading that way.”
The research was published in the journal Nature Communications.
Source: Virginia Tech
