Abstract
The ubiquitous second messenger cyclic guanosine monophosphate (cGMP) plays an important role in metabolism and promotes brown adipocyte differentiation. We showed that ablation of the gene encoding vasodilator-stimulated phosphoprotein (VASP), a major downstream component of the cGMP signaling cascade, increased cellular cGMP content in brown and white adipocytes and mouse embryonic fibroblasts. VASP-deficient cells showed increased activation of Rac1, which in turn increased the abundance of the cGMP-producing enzyme soluble guanylyl cyclase (sGC), the main receptor for nitric oxide. Consequently, loss of VASP caused increased cGMP concentrations and enhanced brown adipocyte differentiation. Consistent with the in vitro data, we found increased energy expenditure in VASP-deficient mice and exposure to cold triggered enhanced lipolysis and cellular respiration in VASP-deficient brown fat cells. In addition, VASP-deficient mice exhibited increased development of brown-like adipocytes in white fat. Our data revealed that a VASP to Rac to sGC negative feedback loop limited cGMP production, thereby regulating adipogenesis and energy homeostasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acclimatization / physiology
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Adipocytes, Brown / metabolism*
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Adipocytes, Brown / physiology
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Adipogenesis / physiology
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Analysis of Variance
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Animals
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Azo Compounds
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Blotting, Western
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Calorimetry, Indirect
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism*
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Cell Differentiation / physiology
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Cell Respiration / physiology
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Cold Temperature
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Cyclic GMP / biosynthesis*
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Energy Metabolism / physiology
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Guanylate Cyclase / metabolism*
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Lipolysis / physiology
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Luciferases
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Mice
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Mice, Knockout
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction / physiology*
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Soluble Guanylyl Cyclase
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rac1 GTP-Binding Protein / metabolism*
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rhoA GTP-Binding Protein / metabolism
Substances
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Azo Compounds
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Cell Adhesion Molecules
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Microfilament Proteins
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Phosphoproteins
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Receptors, Cytoplasmic and Nuclear
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vasodilator-stimulated phosphoprotein
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Luciferases
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rac1 GTP-Binding Protein
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rhoA GTP-Binding Protein
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Guanylate Cyclase
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Soluble Guanylyl Cyclase
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oil red O
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Cyclic GMP