In most circles, brown fat has been overshadowed by its more famous—some would say infamous—relation, white fat. Now, as brown fat is starting to claim its share of the limelight for perhaps playing a role in preventing obesity, its relationship to this notorious cousin is being called into question.
“For years people assumed—I assumed—that there was some sort of fat-cell precursor which could become white or brown,” said Bruce Spiegelman, HMS professor of cell biology at Dana–Farber Cancer Institute. So it was “the biggest shock of my career,” he said, when, by knocking down the expression of a protein called PRDM16 in rodent pre-adipocytes, he saw a result that shattered that assumption—skeletal muscle cells.
In the Aug. 21 issue of Nature, Spiegelman and first author and postdoctoral fellow Patrick Seale report on in vivo fate mapping experiments that establish the existence of a common precursor for brown fat and skeletal muscle. Using mice that express yellow fluorescent protein (YFP) in the descendents of MYF5+ myogenic precursors, they observed YFP in skeletal muscle and mature brown fat cells, but never in white fat cells. “What we assumed was a divergence in the adipose lineage actually is probably a convergence … of quite distinct lineages,” said Spiegelman.
In contrast to white fat, which is optimized for lipid storage, the principal function of brown fat is to burn triglycerides to generate heat, particularly in small mammals and in human newborns, who are vulnerable to the cold. Brown fat reserves decrease significantly with maturity, existing only in small pockets in adults, mostly in the neck and chest. PET scans have shown that these residual pockets are metabolically active, raising the possibility that brown fat regulates overall energy balance and might play a role in controlling body weight.
The suggestion that brown fat has a role to play in preventing obesity and obesity-related disorders is garnering increasing attention, and the Spiegelman lab has been at the forefront of defining the molecular identity of this unique tissue. In 2007, they showed that loss of PRDM16, a zinc-finger protein that is highly enriched in brown fat, triggers the near total attenuation of brown fat characteristics.
Consistent with an important role for PRDM16 in regulating brown fat development, mice deficient in PRDM16 have abnormal brown fat, both morphologically and biochemically. Their fat cells contain unusually large lipid stores (reminiscent of white fat cells) and express low levels of brown fat genes and high levels of muscle genes. According to Spiegelman, in the absence of PRDM16, brown fat looks “strange, dysfunctional, like it was having an identity crisis.”
To determine the mechanism of PRDM16’s activity, Shingo Kajimura, a postdoctoral fellow in the Spiegelman lab, immuno-purified the PRDM16 complex from brown fat cells and discovered that it associated with just one transcription factor, the master fat regulator, PPAR-gamma. “It seemed too good to be true,” said Kajimura.
The Spiegelman lab identified PPAR-gamma in the 1990s as a transcription factor that is both necessary and sufficient to drive adipogenesis. They immediately recognized the significance of the association and were able to show that PRDM16 exercises its effects by binding to and co-activating the transcriptional activity of PPAR-gamma. This is one way that PRDM16 turns on brown fat genes, including uncoupling protein-1 (UCP1), a proton transporter that confers brown fat’s unique ability to uncouple oxidative phosphorylation from ATP synthesis by dissipating the electrochemical gradient and generating heat.
To really harness the slimming power of brown fat, one would likely need to amplify the limited reserves naturally present in adult humans. Spiegelman and his team are working on just that. They are collaborating with the Broad Institute to identify compounds that activate PRDM16 in pre-adipocytes and myoblasts, thereby directing brown fat development. They are also pursuing proof-of-principle adipose transplantation studies in mice. As Spiegelman noted, “You can get [adipose] samples through liposuction, isolate precursors, [genetically] engineer them, and you can put them back. All those things are not that far-fetched for adipose.”
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: American Heart Association, Japan Society for the Promotion of Science, Susan Komen Breast Cancer Foundation, Picower Foundation, National Institutes of Health, and the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases.
