Anti-adiposity impact of phosphodiesterase-5 inhibitor, Sildenafil is possibly through browning of white adipose tissue and FGF21 in obese rats

Background & Aim: Fibroblast growth factor 21 (FGF21) plays an outstanding role in the metabolic homeostasis. It is recently discovered to be released from brown adipocytes. Induction of brown-like adipocytes termed beige/brite within the white adipose tissue (WAT) by means of browning agents is known as “browning process”. These beige/brite cells have plenty of mitochondria with a unique expression of uncoupling protein-1 (UCP1), essential for energy expenditure, and could release FGF21. Being the WAT is excessively expanded in adiposity, the browning agent has gained great interest to combat obesity. The available data on the browning effect of Sildenafil (Sild) in obese rats still a matter of debate. So, we aimed to illustrate this issue. Method & Results: 3 groups of rats were conducted; control group fed standard diet for 9 weeks, high-fat diet (HFD)-fed group for 9 weeks, and Sild-treated group fed HFD for 9 weeks and received Sild (20 mg /kg /each) twice daily, subcutaneously, in the last 3 weeks. Our findings revealed Sild reduced weight gain, fat depots weight, and adiposity index in spite of unchanged food intake in addition to reduced serum triglycerides, free fatty acids, glucose, insulin, and insulin resistance index. The subcutaneous WAT of Sild-treated rats exhibited augmented UCP1, citrate synthase activity, FGF21 and FGF21-Receptor1 expressions with the highest FGF21 serum levels. Conclusions: Our study suggested the protective impact of Sild against adiposity and insulin resistance is possibly through browning impact as well as enhanced FGF21 and FGF21-R1 levels in WAT of obese rats.