Basic Science Newsbrief April

“Molecular origins of brown fat” by Gerald V. Denis – April 2011


Dietary energy can be converted to lipid stores or to heat. However, this simple view of white adipose tissue (storage) or brown adipose tissue (heat) belies the complexity of the transcriptional and metabolic networks that govern this process. In obesity, brown adipose tissue (BAT) is an intensely studied organ because its high metabolic activity offers solutions to the many problems of excess storage: the plethora of metabolic dysfunctions that arise in obese, insulin resistant states. This tissue is ‘brown’ because of the large numbers of mitochondria comprised of iron-rich cytochrome proteins that lend a rust color to each cell. The function of heat production in BAT is controlled by norepinephrine and accomplished by ‘uncoupling proteins’ that amplify inefficiencies in mitochondrial function, rather like disengaging the clutch of the truck and revving the engine hard. This procedure generates a lot of heat and noise but no movement -- its useful outcome is to burn a lot of fuel, which is valuable to combat hypothermia or to consume fuel that is in unhealthy excess in obesity.


Although BAT has long been studied in animal models, its location and metabolic significance in humans was not appreciated until recently, when Positron Emission Tomography (PET) scans, first of adult cancer patients and then of healthy patients, revealed a bright signal from highly metabolically active tissue beside the vertebrae and clavicles that clearly was not tumor tissue. BAT is impressively mobilized by low temperatures; its thermogenic activity maintains core temperature by means of fat catabolism. And in adults, only a small quantity of BAT is capable of converting an enormous amount of energy to heat. These discoveries prompted speculation that BAT could be recruited for therapeutic purposes in obesity.


An important report from Patrick Seale, Bruce Spiegelman and colleagues in Nature in 2008 showed that the zinc finger transcription factor PRDM16 exerts dominant control over a transcriptional switch between two cell fates: muscle and BAT. This observation also suggested that the cell fates of progenitors of muscle and fat were more intertwined in transcriptional networks than previously appreciated. Now, in the January 2011 edition of the Journal of Clinical Investigation, Seale, Spiegelman and colleagues show in mice that PRDM16 is selectively expressed in subcutaneous white adipose tissue (WAT) compared to other depots. This result is significant because subcutaneous WAT protects from metabolic imbalance in obese patients and individuals, and is distinct from visceral WAT, which is generally associated with insulin resistance in humans and animal models. In mouse models, the epididymal depot of male mice is typically the most inflamed in obesity. In functional terms, this means elevated numbers of infiltrating CD11b+ CD11c+ F4/80+ pro-inflammatory macrophages and high levels of local production of pro-inflammatory cytokines, which engender insulin-resistant adipocytes. Subcutaneous fat depots are normally markedly less inflamed than visceral, epididymal and inguinal depots. In humans, this distinction is also commonly recognized as ‘apple-shaped’ fat distribution associated with unhealthy metabolism versus ‘pear-shaped’ distribution that protects against insulin resistance. Interestingly, Seale shows that transgenic expression of PRDM16 in all fat depots leads to its preferential expression in subcutaneous WAT, implying that this depot may have some BAT capability and an intrinsically protective nature.


The therapeutic possibilities of these observations are profound, particularly if investigators can devise safe ways to expand protective depots by PRDM16-dependent transcriptional reprogramming or otherwise re-direct excess energy from storage in visceral WAT to heat production. This area of basic research will be exciting to follow in coming months.



Interested in highlighting your research in the TOS Basic Sciences newsbrief?  Send ideas to the Editors, Dr. Gerald V. Denis ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ) or Dr. Barbara S. Nikolajczyk ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ), for consideration.
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