Obesity represents a heavy burden for healthcare systems alike for which safe and effective therapeutic strategies are still lacking. The increasing prevalence of obesity underscores the need to elucidate the molecular basis of metabolic syndromes pathogenesis. Pharmacological enhancement of cyclic guanosine monophosphate (cGMP) has shown beneficial effects in metabolic disorders models (Mitschke M.M. et la., FASEB J., 2013). cGMP levels are finely regulated by phosphodiesterases (PDEs), enzymes that are responsible of cyclic nucleotides hydrolysis (Campolo F. et al., J. Cell Physiol., 2017). Among them, phosphodiesterase type 5 (PDE5) was recently identified in adipose tissue (Aversa A. et al., J. Sex. Med., 2011) and its inhibition has been demonstrated to induce ¿browning¿ of subcutaneous white adipose tissue in overweight patients (Li S. et al., Metab. Clin. Exper., 2018).
In vitro and in vivo studies have shown that PDE5 inhibition may affect adipogenesis and ameliorate white adipose tissue quality (Mitschke M.M. et la., FASEB J., 2013). Moreover, it has been recently demonstrated that PDE5 inhibition in human and murine models of diabetes improves visceral adipose tissue targeting SIRT1 through a modulation of miR-22-3p expression (Fiore D. et al., J.Cell. Physiol., 2018). A role for PDE5 in adipogenesis was also supported by the observation that PDE5 blockade during preadipocyte differentiation increased intracellular lipid droplets as well as the expression of adipogenic markers (Zhang X. et al., BBRC, 2010). Many evidences suggest an involvement of PDE5 in fat metabolism however its role remains still unclear due the absence of animal models lacking PDE5 in adipose tissue. This proposal aims to clarify the role of the PDE5-regulated cGMP/Protein Kinase G (PKG) system in adipose tissue using PDE5 knockout mouse models. A better elucidation of the role of PDE5 in adipocytes could reveal new therapeutic strategies for fighting obesity and metabolic syndromes.
Preclinical and clinical studies have shown that PDE5 inhibitors (PDE5i) have beneficial effects on improving insulin resistance and glucose metabolism representing a promising therapeutic strategy for the treatment of metabolic disorders.
Several experimental findings suggest that selective PDE5 blockade increases intracellular cGMP levels and concomitantly improves insulin-resistance and peripheral glucose disposal however the lack of Pde5 knockout mouse models hampers a deep understanding of PDE5 contribution in the regulation of glucose and lipid homeostasis.
The development of this research could reveal if PDE5 can be considered a reliable `marker¿ of metabolic dysfunction and/or a mediator of different adipocyte-mediated biological functions. If these results will confirm a role for PDE5 in fat physiology and glucose metabolism, clinical use of selective PDE5 modulators (i.e Sildenafil) could become a promising pharmacological tool to fight metabolic syndromes.
The use of PDE5 knockout mice rise the possibility to perform a deep analysis of the expression and activity of PDE5 in different sites of adipose tissue and also in different metabolic conditions. Given the importance of adipose tissue as a strategic organ in the context of energy homeostasis, a better elucidation of the role of PDE5 in fat metabolism and its pharmacological inhibition could help to clarify the pathophysiology of obesity and metabolic syndrome.