US scientists have discovered a biochemical trigger that switches on brown fat cells so the body burns calories instead of storing them. They suggest the finding brings a new focus to pharmaceutical research aimed at fighting obesity.

Yuriy Kirichok, associate professor of physiology at University of California, San Francisco (UCSF), and colleagues, write about their findings in a paper published in the 12 October online issue of Cell.

Brown fat burns calories to generate heat, unlike white fat, which stores up calories in the all-too-obvious deposits that plague the growing numbers of overweight and obese people.

It wasn’t so long ago that we didn’t know much about brown fat (also known as brown adipose tissue, or BAT). Until recently, we thought the only humans who had it were babies. Now we know that adults have small but important amounts, in various parts of the body.

We also know that low temperatures activate brown fat to generate heat from the energy stored in fat molecules (which is why it is more abundant in hibernating animals such as bears, and small mammals with lots of exposed body surfaces).

In their paper, Kirichok and colleagues describe their discovery of a biochemical mechanism in the protein UCP1 that switches on fat burning in BAT cells. (UCP1 is short for uncoupling protein 1).

In a press statement, Kirichok, the Jack D. and DeLoris Lange Endowed Chair in Systems Physiology at UCSF, suggests it may be possible to develop a drug molecule that keeps the UCP1 switch in the “on” position to increase fat burning in the body.

However, we are still a long way from knowing whether such an approach would be practical for weight control.

Kirichok says while UCP1 may appear to be a good target, the underlying processes that a drug might trigger could be complex.

But regardless of this, he suggests the methods they developed and used in the study, and the information they uncovered, could be very useful for exploring other proteins important for energy metabolism in cells and finding out more about fat burning.

“Low levels of brown fat correlate with obesity,” Kirichok explains.

“We have shown how fatty acids attach directly to UCP1 and help it to break down an electrical potential across the mitochondrial membranes, causing the cell to burn more fat and to generate heat in order to regenerate this potential.”

Cells contain mitochondria, tiny power plants that convert food energy to a cellular fuel known as ATP. This happens through a metabolic mechanism called oxidative phosphorylation, where the chemical energy from fatty acids creates a voltage difference across the membrane that surrounds the mitochondria. This “voltage gradient” provides the energy for making ATP.

If this voltage gradient is short-circuited, then the energy dissipates, thus preventing the production of ATP, and produces heat instead. And here is the clue: because UCP1 acts like a short-circuit.

Brown fat cells are stuffed full of mitochondria that have lots of UCP1 molecules embedded in their membranes. The result is the mitochondria in brown fat cells do not primarily produce ATP but generate heat.

To take a closer look at how UCP1 affects fatty acids in the mitochondria of brown fat, the researchers refined a method called “patch clamping” to track tiny electrical currents. This allowed them to record electrical activity and currents in individual mitochondria.

Although the voltage dissipation role of UCP1, and how this process is activated by long-chain fatty acids (LCFAs), has been known about for a while, what was not clear until this study was how the LCFAs interacted with UCP1 to generate heat (thermogenesis).

Using their refined patch clamping method, Kirichok and colleagues were able directly to track changes in electrical current across mitochondrial membranes containing UCP1 under different experimental conditions, and thus infer the biochemistry of what was going on.

In their paper, they conclude that UCP1 does not just act as a simple channel for electrically charged ions to travel through: the protein actually snares LCFAs and uses them to “shuttle” positively charged hydrogen ions (H+) into the mitochondria.

As more and more H+ ions accumulate inside the mitochondria, thus the electrical potential across its membrane dissipates. This triggers extra cycles of oxidative phosphorylation and fat burning to restore the voltage gradient, thereby generating heat.

Kirichok says he and his team are going to use their refined patch clamp to carry out further investigations into how mitochondria control energy and metabolism.

Written by Catharine Paddock PhD