Researchers report the discovery of a critical early player in the path that turns cells to fat. Given that obesity--defined as an excess amount of body fat relative to lean body mass--is a major health concern in the United States and an increasing problem in the developing world, such a fuller understanding of the molecular processes governing fat tissue formation could ultimately hold clinical importance, according to the researchers.
" We'd like to work our way back to the earliest events [that lead to fat formation]," said Jeffrey Friedman, a Howard Hughes Medical Institute Investigator at Rockefeller University. "Eventually, we want to connect all the dots." Although it remains a speculative notion, he added, "if we knew all the underlying events, we might intervene and alter fat development."
Researchers discovered many years ago that if they added a cocktail of hormonal stimulants to a particular mouse cell line, these so-called 3T3-L1 cells would develop into what appear to be true fat cells in a process known as adipogenesis, Friedman explained. Two decades of research showed that a complex network of transcription factors--genes whose job is to switch other genes on--controls this process. One of the earliest events, those studies showed, is the activation of the transcription factor C/EBPß. But researchers still didn't know what turns C/EBPß on.
An earlier paper by Friedman's team made another advance. They showed that a factor known as Krox20 is active in early fat development and influences the expression of C/EBPß. However, they weren't able to show that it binds the DNA sequence that promotes C/EBPß activity directly, suggesting that it doesn't "flip the switch" on its own.
Now, the researchers show that Krüppel-like factor 4 (KLF4) is the missing link. (KLF4 made headlines recently as one of four ingredients in a cocktail that turns ordinary cells into "induced pluripotent stem cells" that look and act like embryonic stem cells.)
KLF4 can be found in 3T3-L1 cells within 30 minutes after exposure to the standard fat-generating cocktail, the researchers report. Treatments that block KLF4 inhibit fat production and yield lower C/EBPß levels.
Importantly, the researchers found evidence that KLF4 physically binds to the previously discovered factor Krox20. KLF4 then binds directly to the C/EBPß promoter to drive fat production.
Though other factors remain to be discovered, the new report identifies KLF4 as "an essential player in adipocyte differentiation," the researchers concluded. "Our findings place KLF4 among a group of key proadipogenic early transcription factors."
Studies of KLF4 function in living animals will be necessary to evaluate the precise roles of these early transcription factors in fat development and to determine whether there is redundancy in the positions held by various players in the process, the researchers added.
This research is reported in the April issue of Cell Metabolism, a publication of Cell Press.
The researchers include Kivanc¸ Birsoy, Laboratory of Molecular Genetics, Rockefeller University, New York, NY ; Zhu Chen, Laboratory of Molecular Genetics, Rockefeller University, New York, NY, Division of Cardiovascular Diseases, Merck Research Laboratories, Rahway, NJ; and Jeffrey Friedman, Laboratory of Molecular Genetics, Rockefeller University, New York, NY, Howard Hughes Medical Institute, New York, NY.
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