The function of VASP in brown fat
Final Report Abstract
The ubiquitous second messenger cGMP is essential for cardiovascular homeostasis and has recently been shown to control metabolism including brown fat differentiation and mitochondrial biogenesis. Here we have shown that ablation of the VAsodilator-Stimulated Phosphoprotein (VASP), a major downstream component of the cGMP signaling cascade, surprisingly causes a dramatic increase in cellular cGMP levels in different cell types including brown adipocytes, mouse embryonic fibroblasts and white adipocytes. Mechanistically, VASP-deficient cells have increased levels of activated Rac1, which in turn induces the expression of the cGMP-producing enzyme soluble guanylyl cyclase (sGC), the main receptor for nitric oxide. Consequently, loss of VASP causes increased cGMP levels and enhanced brown adipocyte differentiation. Consistent with the in vitro data, we found increased brown adipocyte lipolysis and mitochondrial respiration as well as increased energy dissipation in cold-activated brown fat of VASP-knockout mice. Our data reveal a so far unknown VASP/Rac/sGC feedback loop that controls cGMP levels, thereby regulating adipogenesis and energy homeostasis. Given the crucial role of cGMP for brown fat differentiation, we suggest that the VASP/Rac/sGC feedback loop might be of clinical relevance for developing urgently needed therapies to treat obesity, which has reached pandemic dimensions with more than half a billion adults worldwide affected.
Publications
- (2012). A VASP-Rac-Soluble Guanylyl Cyclase Pathway Controls cGMP Production in Adipocytes. Sci Signal. (5) 239, ra62
Jennissen, K., Siegel, F., Liebig-Gonglach, M., Hermann, M-R., Kipschull, S., van Dooren, S., Kunz, W. S., Fässler, R., and Pfeifer, A.
(See online at https://doi.org/10.1126/scisignal.2002867) - (2013) Analysis of cGMP signaling in adipocytes. Methods Mol Biol 1020, 175-92
Jennissen, K., Haas, B., Mitschke, MM., Siegel, F., and Pfeifer, A.
- A New cGMP Feedback Mechanism that Controls Brown and Beige Adipocyte Differentiation. Keystone Symposium, Adipose Tissue Biology (J5); 2013 Jan 27 – Feb 1; Keystone, Colorado, USA
Siegel, F., Hoffmann, L., Liebig-Gonglach, M., and Pfeifer, A
