The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat–like gene program and thermogenesis in subcutaneous adipose tissues.

Classically, adult humans have been considered not to possess active brown adipose tissue (BAT). However, positron‐emission‐tomography has shown fluorodeoxyglucose uptake that is distributed in such a way ( e.g. , in the neck) that it would seem to be BAT. Until now this has not been supported by direct evidence that these areas truly represented BAT, that is, the presence of the BAT‐unique uncoupling protein‐1 (UCP1). Samples of adipose tissue from the neck of 35 patients undergoing surgery for thyroid diseases were obtained and analyzed. In 1/3 of the subjects (the younger and leaner), distinct islands composed of UCP1 immunoreactive brown adipocytes could clearly be discerned, accounting for up to 1/3 of all adipocytes. The brown‐adipose islands were richlysympathetically innervated (indicating acute central control); adjacent white adipose areas were not. The capillary density was high, implying a high capacity for oxygen delivery. Cells with features of brown adipocyte precursors were found in pericapillary areas. These data demonstrate that human adults indeed possess BAT and thus imply possibilities of future therapeutic strategies for the treatment of obesity, including maintenance of brown adipocytes and stimulation of the growth of preexisting brown precursors.—Zingaretti, M. C., Crosta, F., Vitali, A., Guerrieri, M., Frontini, A., Cannon, B., Nedergaard, J., Cinti, S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 23, 3113–3120 (2009). www.fasebj.org

White and brown adipocytes are believed to occupy different sites in the body. We studied the anatomical features and quantitative histology of the fat depots in obesity and type 2 diabetes-prone C57BL/6J mice acclimated to warm or cold temperatures. Most of the fat tissue was contained in depots with discrete anatomical features, and most depots contained both white and brown adipocytes. Quantitative analysis showed that cold acclimation induced an increase in brown adipocytes and an almost equal reduction in white adipocytes; however, there were no significant differences in total adipocyte count or any signs of apoptosis or mitosis, in line with the hypothesis of the direct transformation of white into brown adipocytes. The brown adipocyte increase was accompanied by enhanced density of noradrenergic parenchymal nerve fibers, with a significant correlation between the density of these fibers and the number of brown adipocytes. Comparison with data from obesity-resistant Sv129 mice disclosed a significantly different brown adipocyte content in C57BL/6J mice, suggesting that this feature could underpin the propensity of the latter strain to develop obesity. However, the greater C57BL/6J browning capacity can hopefully be harnessed to curb obesity and type 2 diabetes in patients with constitutively low amounts of brown adipose tissue.