Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice
Patrick Seale, … , Saverio Cinti, Bruce M. Spiegelman
Patrick Seale, … , Saverio Cinti, Bruce M. Spiegelman
Published December 1, 2010
Citation Information: J Clin Invest. 2011;121(1):96-105. https://doi.org/10.1172/JCI44271.
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Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice

Abstract

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.

Authors

Patrick Seale, Heather M. Conroe, Jennifer Estall, Shingo Kajimura, Andrea Frontini, Jeff Ishibashi, Paul Cohen, Saverio Cinti, Bruce M. Spiegelman

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Figure 4

aP2-Prdm16 mice are protected from obesity and metabolic dysfunction upon high-fat feeding.

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aP2-Prdm16 mice are protected from obesity and metabolic dysfunction up...
(A) Body weights of WT and aP2-Prdm16 mice during 10-week time course of high-fat feeding. (B) MRI was used to analyze body composition (fat and lean mass) in WT and aP2-Prdm16 mice after 16 weeks of high-fat diet. (C) Energy expenditure and food intake was measured for 72 hours in individually housed WT and aP2-Prdm16 mice after 1 week of high-fat diet. Energy expenditure is reported as VO2/mouse/hour. (D) Glucose tolerance test. Blood glucose levels were measured in 16-week high-fat diet–fed WT or aP2-Prdm16 mice after an overnight fast (time 0) and at the indicated times after intraperitoneal injection of glucose. (E) Insulin tolerance test. Blood glucose levels were measured after an overnight fast (time 0) and at the indicated times after an intraperitoneal injection of insulin in mice from D. (F) Immunohistochemistry for Ucp1 (brown stain) protein in ingWAT from WT and aP2-Prdm16 mice after 16 weeks of high-fat diet. The boxed region is shown at higher magnification at right. Ucp1-expressing multilocular and unilocular fat cells are indicated by the arrow and arrowhead, respectively. Original magnification, ×20 (left and middle); ×100 (right). mRNA levels of brown fat–selective genes (Ucp1 and Cidea) were determined in epidWAT, ingWAT, and iBAT from WT and aP2-Prdm16 animals after 16 weeks of high-fat diet. Significance between curves was determined by 2-way ANOVA. Values are mean ± SEM (n = 16 mice per group per experiment). *P < 0.05, **P < 0.01 vs. WT.