Abstract
Brown and beige fat share a remarkably similar transcriptional program that supports fuel oxidation and thermogenesis. The chromatin-remodeling machinery that governs genome accessibility and renders adipocytes poised for thermogenic activation remains elusive. Here we show that BAF60a, a subunit of the SWI/SNF chromatin-remodeling complexes, serves an indispensable role in cold-induced thermogenesis in brown fat. BAF60a maintains chromatin accessibility at PPARγ and EBF2 binding sites for key thermogenic genes. Surprisingly, fat-specific BAF60a inactivation triggers more pronounced cold-induced browning of inguinal white adipose tissue that is linked to induction of MC2R, a receptor for the pituitary hormone ACTH. Elevated MC2R expression sensitizes adipocytes and BAF60a-deficient adipose tissue to thermogenic activation in response to ACTH stimulation. These observations reveal an unexpected dichotomous role of BAF60a-mediated chromatin remodeling in transcriptional control of brown and beige gene programs and illustrate a pituitary-adipose signaling axis in the control of thermogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes, Brown / drug effects
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Adipocytes, Brown / metabolism
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Adipocytes, Brown / ultrastructure
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Adipose Tissue, Beige / metabolism
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Adipose Tissue, Brown / drug effects
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Adipose Tissue, Brown / metabolism*
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Adipose Tissue, White / drug effects
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Adipose Tissue, White / metabolism*
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Adrenocorticotropic Hormone / pharmacology
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Animals
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Binding Sites / genetics
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Cells, Cultured
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Chromatin / genetics
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Chromatin / metabolism*
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Chromosomal Proteins, Non-Histone / deficiency*
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Chromosomal Proteins, Non-Histone / genetics
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Cold Temperature*
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Gene Expression / drug effects
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
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Thermogenesis / drug effects
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Thermogenesis / genetics
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Chromatin
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Chromosomal Proteins, Non-Histone
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Ebf2 protein, mouse
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MRAP protein, mouse
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Membrane Proteins
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Smarcd1 protein, mouse
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Adrenocorticotropic Hormone