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.