Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch.
A clear relationship exists between visceral obesity and type 2 diabetes, whereas subcutaneous obesity is comparatively benign. Here, we show that adipocyte-specific deletion of the coregulatory protein PRDM16 caused minimal effects on classical brown fat but markedly inhibited beige adipocyte function in subcutaneous fat following cold exposure or β3-agonist treatment. These animals developed obesity on a high-fat diet, with severe insulin resistance and hepatic steatosis. They also showed altered fat distribution with markedly increased subcutaneous adiposity. Subcutaneous adipose tissue in mutant mice acquired many key properties of visceral fat, including decreased thermogenic and increased inflammatory gene expression and increased macrophage accumulation. Transplantation of subcutaneous fat into mice with diet-induced obesity showed a loss of metabolic benefit when tissues were derived from PRDM16 mutant animals. These findings indicate that PRDM16 and beige adipocytes are required for the "browning" of white fat and the healthful effects of subcutaneous adipose tissue.
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
Paul
P
Cohen
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Julia D
JD
Levy
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Yingying
Y
Zhang
Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona 60020, Italy.
Andrea
A
Frontini
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Dmitriy P
DP
Kolodin
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Katrin J
KJ
Svensson
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
James C
JC
Lo
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Xing
X
Zeng
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Li
L
Ye
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Melin J
MJ
Khandekar
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Jun
J
Wu
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
Subhadra C
SC
Gunawardana
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Alexander S
AS
Banks
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
João Paulo G
JP
Camporez
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
Michael J
MJ
Jurczak
UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA.
Shingo
S
Kajimura
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
David W
DW
Piston
Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
Diane
D
Mathis
Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Ancona 60020, Italy.
Saverio
S
Cinti
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Cellular and Molecular Physiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06519, USA.
Gerald I
GI
Shulman
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Patrick
P
Seale
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: bruce_spiegelman@dfci.harvard.edu.
Bruce M
BM
Spiegelman
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C521133:Prdm16 protein, mouse; D014157:Transcription Factors