Researchers at the Karolinska Institute may have found a new way to treat obesity and related disorders by targeting the mitochondria. Their findings in mice demonstrate that a specific class of drugs that block mitochondrial function can reverse diet-induced obesity, fatty liver, and diabetes.
The researchers published their study in Nature Metabolism in an article titled, “Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity.”
The first attempts to target mitochondria to treat obesity were reported in the 1930s when more than 100,000 individuals were treated with the uncoupler dinitrophenol (DNP). Although this treatment increased the metabolic rate and reduced obesity, serious side effects prevented DNP from becoming an established treatment. Metformin has also been found to provide an alternate way to inhibit oxidative phosphorylation (OXPHOS). The researchers decided to investigate the connection between beneficial metabolic effects and anticancer activity of drugs targeting mitochondria.
“The oxidative phosphorylation system in mammalian mitochondria plays a key role in transducing energy from ingested nutrients,” the researchers wrote. “Mitochondrial metabolism is dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases and promotes tumor growth. Here, we demonstrate that oral treatment with an inhibitor of mitochondrial transcription (IMT) shifts whole-animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis, and restoration of normal glucose tolerance in male mice on a high-fat diet.”
The research group at the Karolinska Institute led by Nils-Göran Larsson, PhD, professor, recently developed highly specific drug candidates that block mitochondrial function, and thus cellular energy production, to treat cancer.
“Four weeks of treatment led to an unexpected increase in fat metabolism, resulting in a drastic weight loss, a reduction in fat accumulation in the liver, and restored glucose tolerance,” explained postdoctoral researcher Taolin Yuan, PhD, at the department of medical biochemistry and biophysics at the Karolinska Institute.
The treatment was given orally to male obese mice who had been fed a high-fat diet. The effect suggests that blocking the cells’ energy production can reverse obesity and diabetes.
“It’s exciting that we have identified a new potential strategy for treating common diseases like obesity and type 2 diabetes,” said Larsson. “We now aim to further investigate the mechanisms that can explain the drugs’ effect. We have also initiated a collaboration with a biotech company to see if this can be further developed into a treatment for humans. Still, it will be many years before we know if it works,” he concluded.
