Abstract
Induction of brown adipocytes in white fat depots by adrenergic stimulation is a complex genetic trait in mice that affects the ability of the animal to regulate body weight. An 80-fold difference in expression of the mitochondrial uncoupling gene (Ucp1) at the mRNA and protein levels between A/J and C57BL/6J (B6) mice is controlled by allelic interactions among nine quantitative trait loci (QTLs) on eight chromosomes. Overlapping patterns of these QTLs also regulate expression levels of Pgc-1alpha, Pparalpha, and type 2 deiodinase. Independent validation that PPARalpha is associated with Ucp1 induction was obtained by treating mice with the PPARalpha agonist clofibrate, but not from the analysis of PPARalpha knockout mice. The most upstream sites of regulation for Ucp1 that differed between A/J and B6 were the phosphorylation of p38 mitogen-activated protein kinase and CREB and then followed by downstream changes in levels of mRNA for PPARgamma, PPARalpha, PGC-1alpha, and type 2 deiodinase. However, compared to Ucp1 expression, the two- to fourfold differences in the expression of these regulatory components are very modest. It is proposed that small variations in the levels of several transcriptional components of the Ucp1 enhanceosome interact synergistically to achieve large differences in Ucp1 expression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adipocytes / metabolism*
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Adipose Tissue / cytology
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Adipose Tissue, Brown / metabolism*
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Animals
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Chromosomes
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Clofibrate / pharmacology
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Cold Temperature
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Cyclic AMP Response Element-Binding Protein / metabolism
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Gene Expression Regulation*
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Hypolipidemic Agents / pharmacology
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Iodide Peroxidase / genetics
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Iodide Peroxidase / metabolism
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Iodothyronine Deiodinase Type II
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Ion Channels
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Mitochondrial Proteins
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PPAR alpha / agonists
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PPAR alpha / genetics
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PPAR alpha / metabolism
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Quantitative Trait Loci
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RNA, Messenger / analysis
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RNA, Messenger / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors
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Transcription, Genetic
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Uncoupling Protein 1
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Carrier Proteins
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Creb1 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Hypolipidemic Agents
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Ion Channels
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Membrane Proteins
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Mitochondrial Proteins
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PPAR alpha
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PPAR gamma
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Ppargc1a protein, mouse
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RNA, Messenger
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Trans-Activators
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Transcription Factors
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Ucp1 protein, mouse
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Uncoupling Protein 1
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Iodide Peroxidase
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p38 Mitogen-Activated Protein Kinases
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Clofibrate