Role of the <u>VA</u>sodilator-<u>S</u>timulated <u>P</u>hosphoprotein (VASP) in brown fat cell differentiation and function

Abstract

Obesity and associated metabolic disorders result from an imbalance between energy intake and expenditure. In contrast to white fat, which is the major site of energy storage in the body, brown adipose tissue (BAT) is highly vascularized, densely packed with mitochondria and dissipates energy in the form of heat. BAT plays an important role in human neonates in non-shivering thermogenesis as a defense against cold. However, recent studies using positron emission tomography revealed that also adult humans possess metabolically active BAT. BAT activity is controlled by the sympathetic nervous system. Norepinephrine induces both lipolysis as well as the expression of uncoupling protein-1 (UCP-1), which is essential for the thermogenic function of BAT, via increasing cellular cAMP levels. Additionally, NO/cGMP signaling enhances differentiation of brown fat cells through activation of cGMP-dependent protein kinase (PKG). The VAsodilator-Stimulated Phosphoprotein (VASP) is one of the major substrates of PKG. Data presented in this study identify the role of VASP in brown adipocyte differentiation and function. <br /> Surprisingly, in contrast to the suppression of BAT development by PKG ablation, loss of VASP promoted rather than inhibited the differentiation and function of brown fat cells as indicated by increased lipid accumulation, enhanced development of the adipogenic and thermogenic program as well as increased lipolysis and mitochondrial respiration. Mechanistically, this phenotype resulted from increased cGMP production due to enhanced activation of the small GTPase Rac in the absence of VASP. Rac induced the expression of the cGMP-producing enzyme soluble guanylyl cyclase (sGC) and cGMP/PKG-dependent inhibition of RhoA leading to increased insulin signaling in VASP-deficient cells. These effects together with an enhanced activity of the Rac downstream effectors PAK, c-Raf and ERK1/2 promoted brown adipogenesis in the absence of VASP. In line with the in vitro results, BAT of VASP-deficient mice showed an enhanced response to cold stimulation as indicated by increased lipolysis and mitochondrial respiration. <br /> These findings demonstrate an enhanced brown adipogenic differentiation and function in the absence of VASP. Moreover, a novel feedback loop was identified linking the focal adhesion protein VASP to the regulation of cellular cGMP levels via Rac and sGC, thereby regulating adipogenesis and energy homeostasis. This novel VASP/Rac/sGC pathway might be of relevance not only for cellular energy expenditure and the development of therapeutic strategies directed against obesity but also for other diseases that have been associated with altered cGMP levels.