Evidence for two types of brown adipose tissue in humans

Abstract

Based on the seminal observation by Cannon and Nedergaard 1 that human PET scans sometimes depicted a symmetric cold induced uptake of FDG-glucose, three independent studies, published in April 2009, demonstrated metabolically highly active brown adipose tissue (BAT) in adult humans [2][3][4] . Subsequent investigations demonstrated an inverse association of obesity and type 2 diabetes mellitus and the presence of active BAT [5][6][7] . A unique characteristic of BAT is the expression of uncoupling protein 1 (UCP1, also known as thermogenin). Activation of this transmembrane protein by fatty acids in response to adrenergic signaling short-circuits the inner mitochondrial membrane's proton gradient thereby uncoupling oxidative phosphorylation from ATP synthesis. Hence, chemical energy stored in the gradient is dissipated as heat allowing for efficient direct thermogenesis without shivering 8 . This adaptive defense against cold has been examined extensively in rodents and many aspects of BAT development and function have been elucidated. In rodents it is evident 3 that not only the distinct thermogenic BAT organ located in the interscapular region (iBAT) consists of brown adipocytes, but that a second type of brown adipocytes, so-called beige or brite cells can appear in white adipose tissue (WAT) depots in response to cold or 3-adrenergic stimuli 9,10 . Recently, lineage tracing experiments revealed that the two cell types have a different developmental origin 11 . While classical brown adipocytes and skeletal muscle cells arise from precursors in the dermomyotome 12 , beige/brite cells seem to originate from endothelial and perivascular cells within WAT depots [13][14][15] . A recent study by Wu et al suggests that the previously described depots of human BAT are of the beige/brite type and raises the question whether humans altogether lack classical brown adipocytes 16 , this has also been the topic of a recent review 17 . Histomorphological studies performed in the 1970s indicated the existence of brown adipocytes within the interscapular region in human infants and that these disappeared with age 18 . Using a combination of high resolution imaging techniques and morphological and biochemical analyses, we tested the hypothesis that human infants, like small mammals, possess an anatomically distinguishable iBAT depot consisting of classical brown adipocytes, a cell type so far not proven to exist in humans.In an attempt to visualize potential iBAT in humans we performed post mortem MR imaging of eight human infants. Using the fat fraction method 19 we did not only identify BAT depots in the supraclavicular region, but importantly also a fat depot in the interscapular region presenting with an intermediate fat fraction as opposed to the high fat fraction of the surrounding subcutaneous WAT (Supplementary Fig. 1). Using a three dimensional reconstruction we were able to compute the volume of the tissue depot with an average (±SD) volume of 3.6±2.4 ml. Figure 1 displays a representative reconstruction of the iBAT...

Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway

“…[19][20][21] However, adult human BAT is a highly heterogeneous tissue as compared with murine BAT, such that molecular analyses of biopsied adult human BAT samples can be highly confounded by potential contamination of UCP1-negative cells, such as white adipocytes and myocytes. To understand the molecular nature of adult human brown adipocytes at a single-cell resolution, we have recently isolated clonally derived UCP1-positive adipocytes from adult human BAT.…”

Brown adipose tissue and bone

“…The typical BAT organ, the so-called interscapular BAT depot, is located between the shoulder blades of smaller mammals including human infants, 19 and serves to protect the organism in a cold environment by means of non-shivering thermogenesis. The tissue is largely built by classical brown adipocytes, is densely innervated and has a rich blood supply.…”

Evaluation of reference genes for gene expression studies in human brown adipose tissue

“…Secondly, the samples obtained are usually very heterogeneous in the amount of BAT that they contain, analyzed as UCP1 expression levels. [14][15][16][17] If the samples used are very heterogeneous in their amount of BAT, this will increase the variability of any parameter analyzed. Hence, discrete differences in brown adipocytes compared to white adipocytes may be missed due to sample heterogeneity.…”

“…Some examples of reference genes that has been used is TATAbinding protein (TBP), 14,18 cyclophilin A (PPIA), 13,19 b actin (ACTB), 15,20 glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 13 large ribosomal protein P0 (RPLP0) 16,17 and 18S rRNA. 21 In our study, all these reference genes, with the exception of 18S, seemed reasonable robust.…”