Given the potential medical applicationsabout 100 million people suffer from obesity or diabetes in the US aloneresearchers 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 receptora 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 coldhinting 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
|Contact: Madeline McCurry Schmidt|
Scripps Research Institute