Scientists find new calorie-burning switch in brown fat

August 1, 2014

Biologists at The Scripps Research Institute (TSRI) have identified a signaling pathway that switches on a powerful calorie-burning process in brown fat cells.

The study, which is reported in this week's online Early Edition of the Proceedings of the National Academy of Sciences, sheds light on a process known as " thermogenesis," which is of great interest to medical researchers because it naturally stimulates weight loss and may also protect against diabetes.

"This finding offers new possibilities for the therapeutic activation of brown fat thermogenesis," said team leader Anastasia Kralli, associate professor in TSRI's Departments of Chemical Physiology and Cell Biology.

'Revving the Engines'

Most fat cells in our bodies are "white fat" cells that store fat as a reserve energy supply. But we and other mammals also have depots of "brown fat" cells. These apparently evolved not to store but to burn energy—quickly, as a way of generating heat and keeping the body warm in cold conditions, as well as possibly to get rid of excess caloric intake.

Human babies as well as mammals that hibernate have relatively extensive brown fat tissues. Scientists have found in recent years that many adult humans have significant levels of brown fat, which are located mostly in the neck and shoulders, and appear to help regulate body weight and blood sugar.

Low temperatures activate the brown-fat thermogenesis process via the sympathetic nervous system: Nerve ends in brown fat tissue release the neurotransmitter norepinephrine, and that triggers a shift in metabolism within the , which are densely packed with tiny biological energy reactors called mitochondria.

"The mitochondria start generating heat instead of useful chemical energy; it's like revving the engines of a lot of parked cars," said first author Marin Gantner, who was a graduate student in the Kralli laboratory during the study.

Given the potential medical applications—about 100 million people suffer from obesity or diabetes in the US alone—researchers are eager to understand brown fat thermogenesis and how it can be boosted artificially. One clue, reported by other scientists in 1998, is that norepinephrine instructs brown fat cells to express high levels of a protein called PGC-1α, which acts as a general amplifier of energy metabolism and also activates thermogenesis. The Kralli laboratory has shown in past studies that PGC-1α works by activating a molecule called ERRα. But this pathway can't be the only one that triggers thermogenesis, because mice lacking PGC-1α in their fat cells, or ERRα, still show most of the usual thermogenesis response to cold.

A Serendipitous Discovery

In the new study, Gantner, Kralli and their colleagues discovered another thermogenesis activation pathway that works alongside PGC-1α and ERRα.

Originally, however, they were not examining brown fat thermogenesis, but instead were looking for clues to the function of ERRβ, a protein about which little was known at the time, except that it was closely related to ERRα, appeared in brown fat cells, and also worked as a so-called nuclear receptor—a molecular switch for gene activation that can be turned on by small lipophilic molecules or a signaling protein partner.

In the hope of finding ERRβ's signaling partner, the team screened about 18,000 different proteins to see which could biochemically activate it. After accumulating a short list of "hits," the scientists found that one of them, GADD45γ, is normally produced in mouse brown fat cells and becomes especially abundant after exposure to cold—hinting that GADD45γ and ERRβ, much like PGC-1α and ERRα, work together to switch on brown fat thermogenesis.

The team then detailed the signaling in this pathway, from cold-induced norepinephrine release, to upregulation of GADD45γ in brown fat cells, to the activation of ERRβ and another closely related protein, ERRγ, which turned out to be also prevalent in brown and relevant to thermogenesis. "We focused on ERRγ after that," Gantner said.

The team confirmed that the GADD45γ-mediated activation of ERRγ leads to the metabolic shift in brown fat mitochondria that is characteristic of thermogenesis. The scientists also found that transgenic mice lacking GADD45γ can't fully switch on thermogenesis under cold conditions.

In the experiments, GADD45γ acted synergistically with PGC-1α to activate brown fat cell activity. "You have to add them together to get the full effect," said Kralli, suggesting that ideally, one would stimulate both pathways to boost brown fat .

Explore further: New clue helps explain how brown fat burns energy

More information: "GADD45γ regulates the thermogenic capacity of brown adipose tissue" by Marin L. Gantnera, Bethany C. Hazena, Juliana Conkrightb, and Anastasia Krallia. July 31, 2014. Proceedings of the National Academy of Sciences. www.pnas.org/content/early/201 … /1406638111.abstract

Related Stories

New clue helps explain how brown fat burns energy

July 3, 2014
The body contains two types of fat cells, easily distinguished by color: White and brown. While white fat serves to store excess calories until they're needed by the body, brown adipocytes actually burn fat by turning it ...

Researchers discover that brown fat protects against diabetes and obesity in humans

July 23, 2014
Researchers at the University of Texas Medical Branch at Galveston have shown for the first time that people with higher levels of brown fat, or brown adipose tissue, in their bodies have better blood sugar control, higher ...

Some fat cells can feel the cold

July 2, 2013
(Medical Xpress)—To survive in cold environments, mammals burn fat to produce heat. The breakdown of fat helps prevent obesity and related metabolic diseases, such as diabetes. Bruce Spiegelman and his colleagues at Harvard ...

Immune system molecules may promote weight loss, study finds

June 5, 2014
The calorie-burning triggered by cold temperatures can be achieved biochemically – without the chill – raising hopes for a weight-loss strategy focused on the immune system rather than the brain, according to a new study ...

Activating the immune system could treat obesity and diabetes

June 5, 2014
Obesity is a worldwide epidemic that is causing alarming rates of diabetes and cardiovascular disease, but currently there is a lack of effective drug treatments. Two unrelated studies published by Cell Press June 5th in ...

Researchers identify specific causes of brown fat cell 'whitening'

April 9, 2014
Boston University researchers have learned new information about the consequences of overeating high-calorie foods. Not only does this lead to an increase in white fat cell production, the type prominent in obesity, but it ...

Recommended for you

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.