title: A VASP-Rac-soluble guanylyl cyclase pathway controls cGMP production in adipocytes.
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.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Bonn, 53105 Bonn, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Jennissen
authors.forename: Franziska
authors.initials: F
authors.lastname: Siegel
authors.forename: Michaela
authors.initials: M
authors.lastname: Liebig-Gonglach
authors.forename: Michaela-Rosemarie
authors.initials: MR
authors.lastname: Hermann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kipschull
authors.forename: Sander
authors.initials: S
authors.lastname: van Dooren
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
mesh_terms: D000064:Acclimatization / Q000502:physiology; D052437:Adipocytes, Brown / Q000378:metabolism* / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001391:Azo Compounds; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D019069:Cell Respiration / Q000502:physiology; D003080:Cold Temperature; D006152:Cyclic GMP / Q000096:biosynthesis*; D004734:Energy Metabolism / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D008066:Lipolysis / Q000502:physiology; D008156:Luciferases; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D001391:Azo Compounds; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D000098662:Vasodilator-Stimulated Phosphoprotein; D008156:Luciferases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C011049:oil red O; D006152:Cyclic GMP