Ordinary fat cells in obese animals can be induced to burn energy stores, generating substantial heat, according to a preclinical study by Weill Cornell Medicine investigators.
In the study, published Feb. 23 in Nature Metabolism, the researchers showed that in fat cells called white adipocytes, high levels of fatty acids from fat stores, in the presence of a key enzyme called AAC, can trigger a process that uses fat to produce heat and increase energy expenditure. They demonstrated that this process can occur in obese mice - implying that it could yield significant weight loss over time.
"There is still a lot of research to do, but in principle this approach to treating obesity might be very effective and safe," said study senior author Shannon Reilly, an assistant professor of metabolic health in medicine and a member of the Joan and Sanford I. Weill Center for Metabolic Health at Weill Cornell Medicine. "Current weight-loss medications work by reducing hunger but sometimes have unpleasant digestive side effects. This new approach complements these existing therapies and thus could potentially be used in conjunction with lower doses to minimize unwanted side effects."
The concept of reducing fat simply by converting it into heat has tantalized scientists for generations. Virtually all cell types in animals use tiny oxygen-consuming engines called mitochondria to convert sugars and fats - basic energy sources - into a cellular currency called ATP. This ATP-making process normally yields some heat as a byproduct, however when the process is "uncoupled" from ATP generation, it only produces heat. Uncoupling allows the engine to burn fat without constraint.
A specialized type of adipocyte called a brown adipocyte evolved to use uncoupling to produce heat to keep mammals warm. Brown adipocyte activity protects against obesity-associated diseases, including diabetes and heart disease. Unfortunately, these cells are relatively scarce and inactive in adults, especially in the context of overweight and obesity. Thus, activating them has not proven to be a feasible target to promote weight loss.
Furthermore, weight-loss drugs that work by increasing uncoupling throughout the body, while effective, can be very dangerous. The uncoupling drug 2,4-dinitrophenol, available over the counter in the United States for several years until it was banned in 1938, had adverse effects including fatal overheating. Amphetamines and other weight-reducing stimulants have similar effects and are also addictive.
In the new study, Reilly, who is also the Ralph L. Nachman, MD Research Scholar at Weill Cornell Medicine, and her team investigated the possibility of inducing uncoupling just where the fat is, in white adipocytes. These cells are overly abundant in obesity, making them an attractive therapeutic target for weight loss. Previous studies in mice that suggested only brown adipocytes produce heat were biased by housing of the animals at room temperature, the temperature at which internal and external heat exchange is balanced in humans.
However, because mice are much smaller, they lose more heat to their environment. Housing mice at 86 degrees Fahrenheit, analogous to "room temperature" for these animals, changes the pathways they depend on to stay warm, shifting their metabolism to be more like humans'.
"Working at 86 degrees Fahrenheit is particularly pleasant in the winter, like collecting data on a tropical island," said A. Melisa Aksu, a research technician and one of the co-first authors of the study.
Under these warmer conditions, Reilly and her team were able to detect heat production in white adipocytes. The scientists looked in particular at a natural process called lipolysis, in which white adipocytes mobilize their fat stores in response to signals that the body needs some of their packed-away energy. The researchers found that when lipolysis occurs, there is a high degree of uncoupling in white adipocyte mitochondria.
They showed that this uncoupling is the result of fatty acids - the fats liberated by lipolysis - interacting with an enzyme known as AAC, an ATP carrier. AAC is an evolutionary cousin of the specialized uncoupling protein found in brown adipocytes, but its relevance to heat production through uncoupling had not been demonstrated in mammals.
"Uncoupling in white adipocytes has been observed in prior studies, but the mechanism was unknown," Reilly said. "The consensus in the field had been that it couldn't be a relevant source of energy consumption or heat production."
Testing that view experimentally, the researchers activated lipolysis to increase fatty acids and induce uncoupling by AAC in the white adipocytes of obese mice. They performed the experiments under conditions that effectively shut down any other warming effects from brown adipocytes and muscle movements. This was enough to cause an obvious rise in the animals' body temperatures compared to control animals - an energy-burning effect that would be expected, over time, to induce measurable weight loss.
The findings suggest that white fat cells have an innate ability to convert fat to heat, despite lacking the specializations found in brown adipocytes, which enhance their capacity to generate heat.
Reilly now hopes to find a viable method for boosting this uncoupling ability selectively in white adipocytes.
"The idea," she said, "would be to cause a small increase in heat production, just in the fat cells, which over time could be a very effective and safe way to promote weight loss."
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, through grant number R01DK126944.
Jim Schnabel is a freelance writer for Weill Cornell Medicine.f
