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Sci. Signal., 28 August 2012
Vol. 5, Issue 239, p. ra62
[DOI: 10.1126/scisignal.2002867]

RESEARCH ARTICLES

A VASP-Rac–Soluble Guanylyl Cyclase Pathway Controls cGMP Production in Adipocytes

Katja Jennissen1, Franziska Siegel1*, Michaela Liebig-Gonglach1*, Michaela-Rosemarie Hermann1,2*, Stefanie Kipschull1, Sander van Dooren1, Wolfram S. Kunz3, Reinhard Fässler2, and Alexander Pfeifer1,4{dagger}

1 Institute of Pharmacology and Toxicology, University of Bonn, 53105 Bonn, Germany.
2 Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
3 Division of Neurochemistry, Department of Epileptology, University of Bonn, 53105 Bonn, Germany.
4 Pharma-Center, University of Bonn, 53105 Bonn, Germany.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: alexander.pfeifer{at}uni-bonn.de

Citation: K. Jennissen, F. Siegel, M. Liebig-Gonglach, M.-R. Hermann, S. Kipschull, S. van Dooren, W. S. Kunz, R. Fässler, A. Pfeifer, A VASP-Rac–Soluble Guanylyl Cyclase Pathway Controls cGMP Production in Adipocytes. Sci. Signal. 5, ra62 (2012).

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