Researchers develop mild mitochondrial uncouplers to treat obesity

Researchers have developed experimental drugs that encourage the mitochondria in our cells to work a little harder and burn more calories. The findings could open the door to new treatments for obesity and improve metabolic health.

Obesity is a global epidemic and a risk factor for many diseases, including diabetes and cancer. Current obesity drugs require injections and can cause side effects, so a safe way to boost weight loss could offer significant public health benefits.

The study, led by Associate Professor Tristan Rawling from the University of Technology Sydney (UTS), has just been published in Chemical Sciencethe flagship journal of the Royal Society of Chemistry of the United Kingdom, where it was highlighted as “pick of the week”.

The research team, from UTS and Memorial University of Newfoundland, Canada, focused on ‘mitochondrial uncouplers’. These are molecules that make cells burn energy less efficiently and release fuel as heat instead of converting it into energy the body can use.

Mitochondria are often called the powerhouses of the cell. They convert the food you eat into chemical energy, called ATP or adenosine triphosphate. Mitochondrial uncouplers disrupt this process, causing cells to consume more fat to meet their energy needs.”

Tristan Rawling, Associate Professor, University of Technology Sydney

“It’s described as a hydroelectric dam. Normally, the water from the dam flows through turbines to generate electricity. The decouplers act as a leak in the dam, letting some of that energy bypass the turbines, so it’s lost as heat, instead of generating useful power.”

Compounds that cause mitochondria to uncouple were first discovered about a century ago, yet these early drugs were deadly poisons that caused overheating and death.

“During the First World War, munitions workers in France lost weight, had high temperatures and some died. Scientists discovered that this was caused by a chemical used in the factory called 2,4-Dinitrophenol or DNP,” said Associate Professor Rawling.

“DNP disrupts mitochondrial energy production and increases metabolism. It was marketed briefly in the 1930s as one of the first weight loss drugs. It was highly effective but was eventually banned because of its severe toxic effects. The dose required for weight loss and the lethal dose are dangerously close,” he said.

In the new study, the researchers created safer “gentle” mitochondrial uncouplers by fine-tuning the chemical structure of the experimental molecules, allowing them to fine-tune how strongly the molecules boost cellular energy use.

While some of the experimental drugs increased mitochondrial activity without harming cells or disrupting their ability to produce ATP, others created the same dangerous uncoupling seen with the older, toxic compounds.

This discovery allowed researchers to better understand why safer molecules behave differently. Mild mitochondrial uncouplers slow the process down to a level the cells can handle, protecting against adverse effects.

Another benefit of mild mitochondrial uncouplers is that they reduce oxidative stress in the cell. This could improve metabolic health, provide anti-aging effects and protect against neurodegenerative diseases such as dementia.

While the work is still at an early stage, the research offers a framework for designing a new generation of drugs that could gently induce mitochondrial uncoupling and reap the benefits without the risks.