An experimental drug that changes the way cells burn fuel helped obese mice lose body fat and, at higher doses, partially improved how their bodies handled sugar, according to a new study from the University of Alberta in Canada. The findings suggest a potential new direction for future obesity treatments that would work by rewiring metabolism rather than simply cutting appetite.
The research, Targeting Metabolic Dysregulation in Obesity: The Interplay Between Pyruvate Dehydrogenase and Weight Loss, part of a master’s thesis by Indiresh A. Mangra-Bala, focused on a small molecule called dichloroacetate, or DCA. For decades, scientists have known that DCA can push cells to burn sugar more completely in their “power stations,” the mitochondria. In this study, the question was simple but ambitious: if you force the body to use sugar differently after obesity has already developed, can you actually reduce fat and improve health?
At the heart of the work is an enzyme system called the pyruvate dehydrogenase complex, or PDH. In simple terms, PDH is like a gate that decides what happens to sugar once it enters the cell. When the gate is open, sugar is sent into the mitochondria and burned for energy. When the gate is closed, much of that sugar is diverted into other pathways that can end up as fat or as lactate in the blood. In obesity and diabetes, that metabolic gate tends to be “closed” more often than it should be, because a family of enzymes called pyruvate dehydrogenase kinases, or PDHKs, act like brakes on PDH.
High-fat diet for ten weeks
DCA works by blocking PDHKs, which in theory removes some of those brakes and keeps the PDH gate more open. The new study investigated the effects of applying this concept to obese animals. Researchers first fed male and female mice a high-fat diet for ten weeks until they became obese. Only then did they begin treating the animals with DCA to mimic a real-world situation in which patients are already overweight before a drug is started.
The mice were then followed for four weeks on different DCA regimens. In one group, the animals received a relatively high dose of DCA in their drinking water. Under this treatment, the obese mice lost a meaningful amount of weight, and careful measurements showed that most of that loss came from fat rather than from muscle. When the mice were given a standard sugar challenge, their blood sugar spiked less and returned to normal more quickly, a sign of better glucose tolerance. Blood tests also showed lower levels of inflammatory markers that are usually elevated in obesity, and the animals had higher levels of ketone bodies, which indicates that they were burning more fat for fuel.
However, even with these improvements, the deeper picture was more complicated. When scientists measured insulin sensitivity, which looks at how well the body responds to its insulin, they did not see a major improvement. That means the sugar curve looked better, but not because the cells suddenly became much more responsive to insulin. On top of that, the high-dose DCA water affected the animals’ behavior. The mice ate less and drank less, most likely because the medicated water was unpalatable. Some of the weight loss may therefore have been due to reduced food and water intake rather than pure metabolic rewiring.
Tests showed a reduction in fat mass
To address this problem, the team tested a different strategy. A second group of obese mice received a lower concentration of DCA in their water, combined with a once-daily injection of the drug. This protocol was designed to reduce the taste issue but still deliver enough medicine to the body. On this regimen, the mice again lost weight, and body composition tests showed a reduction in fat mass. Yet this time the broader metabolic benefits largely disappeared. There were no clear improvements in glucose tolerance, no measurable gains in insulin sensitivity, and no major changes in inflammatory markers.
That contrast is one of the most important results of the thesis. It suggests that there may be a threshold of PDH “activation” needed to genuinely repair disturbed metabolism in obesity. The high dose reached that threshold but came with side effects and confounding factors such as reduced drinking and eating. The lower dose and injection schedule still helped trim fat, but it did not appear to be strong enough to address the underlying metabolic damage on its own.
The researcher also looked at what DCA does directly to fat cells. Using a standard fat cell line grown in the laboratory, the team showed that DCA reduced the amount of fat stored inside these cells. Intriguingly, this reduction happened even when the usual DCA target, one of the PDHK enzymes, was partially knocked down, and even when the on or off status of PDH did not change in the way one would expect. That finding hints that DCA is acting through multiple switches. Instead, it may be tugging on several parts of the cell’s fuel network at the same time, something drug developers will have to understand before designing safer medicines that work in similar ways.
The author of the thesis stresses that this is early-stage work in animals, not a human trial. DCA itself is not an approved treatment for obesity, diabetes, or cancer, and clinical experience in other conditions has raised concerns about side effects such as nerve damage and liver problems when the drug is used at higher doses or for long periods. No one should see it as a new diet pill ready for the pharmacy shelf.
What the study does provide is a demonstration of the concept. It shows that targeting the PDH–PDHK axis can change body fat and, when pushed strongly enough, can also improve some aspects of how the body handles sugar and inflammation. At the same time, the results are a warning that simply nudging metabolism is not enough. Any future drug in this family will need to be carefully designed so that it is powerful enough to reset metabolism yet gentle enough that patients continue to eat and drink normally and do not develop serious side effects.
With obesity and type 2 diabetes on the rise in Israel and around the world, current medications such as GLP-1 agonists have opened a new chapter in treatment by lowering appetite and changing hormones. The Canadian research delves deeper into the inner workings of the cell, questioning whether altering our bodies' decision to burn sugar or store fat could provide an alternative approach. For now, dichloroacetate remains an experimental tool. But the gate it targets in the cell, and the broader idea of adjusting the body’s “fuel choice” rather than only its hunger signals, may inspire the next generation of obesity drugs.