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.

Public Health Relevance

Obesity and its adverse cardiovascular consequences represent major public health problems. Data from experimental models and human studies suggest that a class of medications known as phosphodiesterase type 5 inhibitors may increase the metabolic rate of adipose tissue and improve metabolic health. Thus, we propose a clinical trial to examine the effects of a once-daily phosphodiesterase type 5 inhibitor in obese adults.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Laughlin, Maren R
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Vanderbilt University Medical Center
United States
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