Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice.
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.
Institute for Diabetes, Obesity, and Metabolism and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. sealep@upenn.edu
Patrick
P
Seale
Heather M
HM
Conroe
Jennifer
J
Estall
Shingo
S
Kajimura
Andrea
A
Frontini
Jeff
J
Ishibashi
Paul
P
Cohen
Saverio
S
Cinti
Bruce M
BM
Spiegelman
D002001:Adipose Tissue, Brown / Q000502:physiology; D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000235:genetics; D050151:Subcutaneous Fat / Q000502:physiology*; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D014018:Tissue Distribution; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015430:Weight Gain / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D004041:Dietary Fats; C521133:Prdm16 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors