Abstract
Brown adipose tissue is a thermogenic organ that dissipates stored energy as heat to maintain body temperature. This process may also provide protection from development of diet-induced obesity. We report that the bioactive lipid mediator lysophosphatidic acid (LPA) markedly decreases differentiation of cultured primary brown adipocyte precursors, whereas potent selective inhibitors of the LPA-generating enzyme autotaxin (ATX) promote differentiation. Transgenic mice overexpressing ATX exhibit reduced expression of brown adipose tissue-related genes in peripheral white adipose tissue and accumulate significantly more fat than wild-type controls when fed a high-fat diet. Our results indicate that ATX and its product LPA are physiologically relevant negative regulators of brown fat adipogenesis and are consistent with a model in which a decrease in mature peripheral brown adipose tissue results in increased susceptibility to diet-induced obesity in mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adipogenesis* / drug effects
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Adipokines / blood
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Adipose Tissue, Brown / drug effects
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Adipose Tissue, Brown / immunology
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Adipose Tissue, Brown / metabolism*
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Adipose Tissue, Brown / pathology
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Animals
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Cells, Cultured
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Cytokines / blood
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Diet, High-Fat / adverse effects*
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Embryo, Mammalian
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Enzyme Inhibitors / pharmacology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gene Expression Regulation / drug effects
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Ion Channels / genetics
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Ion Channels / metabolism
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Lysophospholipids / metabolism*
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Male
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Mice
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Mice, Transgenic
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Obesity / etiology
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Obesity / immunology
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Obesity / metabolism*
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Obesity / pathology
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Phosphoric Diester Hydrolases / chemistry
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Phosphoric Diester Hydrolases / genetics
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Phosphoric Diester Hydrolases / metabolism*
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RNA, Messenger / metabolism
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Random Allocation
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Subcutaneous Fat / drug effects
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Subcutaneous Fat / immunology
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Subcutaneous Fat / metabolism
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Subcutaneous Fat / pathology
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Uncoupling Protein 1
Substances
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Adipokines
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Cytokines
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Enzyme Inhibitors
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Ion Channels
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Lysophospholipids
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Mitochondrial Proteins
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RNA, Messenger
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Recombinant Proteins
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Uncoupling Protein 1
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Phosphoric Diester Hydrolases
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alkylglycerophosphoethanolamine phosphodiesterase
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lysophosphatidic acid