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The origin and the true nature of the multilocular cells rich in mitochondria and expressing UCP1 that appeared in WAT upon cold acclimation or β3-AR stimulation has yet to be determined. The presence of brown adipocyte progenitors in WAT has been hypothesized by studies showing that 10–15% of the precursor cells isolated from mouse WAT differentiate into brown adipocytes in culture (Klaus et al., 1995) and that brown adipocyte progenitors are present in human WAT depots (Digby et al., 1998). Another hypothesis suggests that a few unilocular white adipocytes are indeed “masked” brown adipocytes that can recover a brown phenotype in response to a SNS stimulation such as that induced by cold exposure. Himms-Hagen et al. (2000), studying the effect of CL 316243 in rats, suggested that the multilocular cells expressing UCP1 that appeared in the WAT were different from the classical brown adipocytes and postulated that they might derive, at least in part, from pre-existing unilocular adipocytes. Orci et al. (2004) showed that hyperleptinemia in rats induces the transformation of white adipocytes into so-called post-adipocytes (or fat-oxidizing machines), which have the phenotype of brown adipocytes. Other effectors that enhance brown adipocyte recruitment in white depots include synthetic PPARγ ligands such as thiazolidinediones (Wilson-Fritch et al., 2004; Xue et al., 2005; Vernochet et al., 2009; Petrovic et al., 2010). Overall, it seems very likely that, at least in some WAT depots, brown adipocytes can emerge from differentiation of brown adipocyte precursors/preadipocytes or transdifferentiation of existing white adipocytes (Jimenez et al., 2003; Zingaretti et al., 2009). The precise origins of brown cells in WAT will likely be determined within the very near future since recent studies have started to identify the progenitors of brown as well as white adipocytes. In the case of brown cells, tracing the lineages arising from progenitors expressing the myogenic transcription factor, myf5 have clearly shown that brown adipocytes within the interscapular BAT depot of mice share an origin with skeletal myocytes that arise from the dermomyotome (Seale et al., 2008). In these investigations, the brown cells recruited to WAT in response to the cold were myf5 negative, thus unlikely to share a myogenic origin. Two independent studies employing different procedures have identified white progenitors within the microvasculature of adipose tissue and not of other tissues (Rodeheffer et al., 2008; Tang et al., 2008). These progenitors express markers of mural cells (pericytes) that arise from the sclerotome and give rise to several other cell types of the vasculature. It is conceivable; therefore, that recruitment of WAT brown adipocytes is due to a selective activation of these mural cells to progress along a brown lineage in response to effectors that are activated by the recruitment-associated stimulus. Possible effectors include BMP7, which has been shown to induce the conversion of mesenchymal stem cells to brown adipocytes in culture and is required for BAT formation in mice (Tseng et al., 2008).Go to:
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