Effect of PDE5 Inhibition on Adipose Metabolism in Humans

ABSTRACT
Obesity is characterized by an excess of white adipose tissue (WAT), which has low metabolic activity. Recent
studies demonstrate that cells in WAT can be driven toward a metabolically active brown adipose phenotype
(termed “beiging”), which is causally associated with weight loss and improved insulin sensitivity.
Pharmacologic therapies to stimulate beiging of WAT and activation of brown adipose tissue (BAT) may
reduce cardiovascular and diabetes risk in obesity. Cyclic guanylate monophosphate (cGMP) signaling may
positively influence adipose tissue metabolism. cGMP serves as the second messenger for the natriuretic
peptides, which are reduced in obesity. Wild type mice exposed to exogenous natriuretic peptide have
increased expression of brown adipocyte-associated genes in WAT and BAT, providing evidence for beiging of
WAT and activation of BAT. A safe and inexpensive strategy to enhance cGMP signaling in humans is
inhibition of an enzyme involved in its breakdown, phosphodiesterase type 5A (PDE5). Data on the effects of
PDE5 inhibition on WAT and BAT function in humans are limited. One barrier to human studies has been the
lack of a non-invasive method to detect both activated BAT and beiging of WAT. We have developed and
published a magnetic resonance imaging technique to quantify the full spectrum of lipid metabolism in WAT
and BAT using fat signal fraction (FSF). In preliminary data, we show that 1) cold exposure (a cGMP stimulus)
causes beiging of WAT in humans, 2) chronic PDE5 exposure improves insulin sensitivity in obese adults and,
3) mice treated with PDE5 inhibitors exhibit increased energy expenditure and resistance to weight gain. We
hypothesize that PDE5 inhibition in obese adults will result in beiging of WAT and activation of BAT. We will
perform non-invasive imaging and subcutaneous fat aspiration to link changes in adipose imaging and gene
expression at the same anatomic site for the first time. We will randomize participants to tadalafil (20mg/day) or
placebo for 3 months. Endpoints will be measured at room temperature and after a cold exposure protocol,
which will allow us to determine whether a chronic increase in cGMP tone through PDE5 inhibition “primes”
BAT and WAT for activation in the setting of a natriuretic peptide stimulus. Aim 1 will examine the effect of
PDE5 inhibition on adipose metabolism. We will randomize 100 obese individuals to tadalafil or placebo for 3
months. The primary endpoint is WAT FSF at room temperature. Aim 2 will examine the effect of PDE5
inhibition on subcutaneous WAT gene expression. The primary endpoint will be change in WAT UCP1
expression at 3 months. A secondary aim will link data from Aims 1 and 2 to examine the association between
change in FSF and WAT gene expression after PDE5 inhibition and cold exposure. The importance of this aim
is to establish for the first time in humans the relationship between imaging and molecular markers of adipose
metabolism. Repurposing PDE5 inhibitors could be an important adjunct to lifestyle interventions in an effort to
counter cardiovascular and diabetes risk in obese individuals.

Grant Number: 5R01DK124845-05
NIH Institute/Center: NIH
Principal Investigator: Evan Brittain