Stimulation of thermogenic pathways appears to be a promising approach to find new ways of tackling metabolic diseases like obesity and diabetes mellitus type 2. Thermogenic, weight reducing and insulin sensitizing effects of phosphodiesterase 5 (PDE 5) inhibitors have recently been postulated, suggesting that modulators of endogenous cGMP signaling have the therapeutic potential to treat metabolic disorders. However, most studies have been performed in vitro or in animals that were not glucose intolerant. We, thus, aimed to test the metabolic effects of the PDE 5 inhibitor sildenafil by treating diet-induced obese (DIO) mice orally for 8 days. Surprisingly, our results revealed no changes in body temperature, brown adipose tissue (BAT) thermogenesis and gene expression in BAT and inguinal white adipose tissue (iWAT), thus excluding a thermogenic or 'browning' effect of sildenafil in preexisting obesity. In contrast, sildenafil-treated DIO mice displayed changes in liver metabolism and glucose homeostasis resulting in impaired glucose tolerance (P < 0.05), demonstrating for the first time an unfavorable metabolic effect of increased hepatic cGMP signaling in obesity. As sildenafil is commonly prescribed to treat pulmonary arterial hypertension and erectile dysfunction in diabetic and/or obese patients, follow up studies are urgently required to re-evaluate the drug safety.