Brown Adipose YY1 Deficiency Activates Expression of Secreted Proteins Linked to Energy Expenditure and Prevents Diet-Induced Obesity.
Mitochondrial oxidative and thermogenic functions in brown and beige adipose tissues modulate rates of energy expenditure. It is unclear, however, how beige or white adipose tissue contributes to brown fat thermogenic function or compensates for partial deficiencies in this tissue and protects against obesity. Here, we show that the transcription factor Yin Yang 1 (YY1) in brown adipose tissue activates the canonical thermogenic and uncoupling gene expression program. In contrast, YY1 represses a series of secreted proteins, including fibroblast growth factor 21 (FGF21), bone morphogenetic protein 8b (BMP8b), growth differentiation factor 15 (GDF15), angiopoietin-like 6 (Angptl6), neuromedin B, and nesfatin, linked to energy expenditure. Despite substantial decreases in mitochondrial thermogenic proteins in brown fat, mice lacking YY1 in this tissue are strongly protected against diet-induced obesity and exhibit increased energy expenditure and oxygen consumption in beige and white fat depots. The increased expression of secreted proteins correlates with elevation of energy expenditure and promotion of beige and white fat activation. These results indicate that YY1 in brown adipose tissue controls antagonistic gene expression programs associated with energy balance and maintenance of body weight.
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Francisco
F
Verdeguer
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Meghan S
MS
Soustek
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Maximilian
M
Hatting
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Sharon M
SM
Blättler
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Devin
D
McDonald
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Joeva J
JJ
Barrow
Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA Pere_Puigserver@dfci.harvard.edu.
Pere
P
Puigserver
D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D050154:Adiposity / Q000235:genetics / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D004032:Diet; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control*; D022722:Thermogenesis / Q000235:genetics; D050986:YY1 Transcription Factor / Q000172:deficiency / Q000378:metabolism*
D024101:Mitochondrial Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse