PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial

J Clin Endocrinol Metab. 2016 Apr;101(4):1525-34. doi: 10.1210/jc.2015-4252. Epub 2016 Mar 10.


Context: Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients.

Objective: To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs).

Design: Randomized, double-blind, placebo-controlled study in type 2 diabetes.

Patients and intervention: A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected.

Main outcome and measures: Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT.

Results: Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafil's modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile.

Conclusions: Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / drug effects*
  • Adiposity / genetics
  • Adult
  • Aged
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 5 / chemistry*
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Double-Blind Method
  • Flow Cytometry
  • Humans
  • Male
  • Mice
  • Mice, Obese
  • MicroRNAs / genetics*
  • Middle Aged
  • Obesity, Abdominal / drug therapy*
  • Obesity, Abdominal / metabolism
  • Obesity, Abdominal / pathology
  • Phosphodiesterase 5 Inhibitors / pharmacology*
  • Real-Time Polymerase Chain Reaction
  • Sildenafil Citrate / pharmacology*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*


  • MIRN22 microRNA, human
  • MicroRNAs
  • Phosphodiesterase 5 Inhibitors
  • Sildenafil Citrate
  • Cyclic Nucleotide Phosphodiesterases, Type 5
  • PDE5A protein, human
  • SIRT1 protein, human
  • Sirtuin 1