Sildenafil Activates Browning of White Adipose and Improves Insulin Sensitivity

Obesity and metabolic disease result when energy intake consistently exceeds energy expenditure. One appealing new target for treatment is the activation of brown adipose tissue (BAT), an organ recently found to be functional in adult humans. Brown adipocytes selectively express uncoupling protein 1 (UCP1), which renders the inner membrane of mitochondria leaky, thereby diverting chemical energy from ATP generation to heat production. Interest in BAT has been spurred by the recognition that in addition to classical BAT depots, other brown-fat-like cells are present in the subcutaneous white adipose tissue (WAT) in animals and also in humans.These cells have structural and functional properties that resemble brown adipocytes, and they are referred to as beige or 'brite' (brown-in-white) adipocytes. Interestingly, browning of WAT can be induced in animals and humans by physiological stimuli such as cold exposure, which increases adrenergic tone, and by exercise, which selectively drives WAT browning through irisin, an exercise-induced myokine. In addition b-adrenergic drugs and other pharmacological agents,such as prostaglandins, can induce browning of white adipose tissue. More recently, one study showed that treatment of C57BL/6 mice with phosphodiesterase inhibitor sildenafil (12 mg/kg/d) for 7 d caused 4.6-fold increase in uncoupling protein-1 expression and promoted establishment of a brown fat cell-like phenotype ("browning") of WAT in vivo. Therefore, the investigators hypothesized that sildenafil can promote browning of white adipose tissue and improves insulin sensitivity in human adults.

The study subjects will be taken placebo (first stage) and sildenafil (second stage) intervention for 7 days, respectively afterward.Subcutaneous fat tissue and muscle samples will be obtained by biopsy from some individuals and measure the browning of white adipose tissue and insulin signaling.The insulin sensitivity will be tested by insulin clamp assay before and after each intervention, respectively. In addition,blood samples for biochemical analysis will be obtained before and after each intervention, respectively.

The browning of white adipose tissue will be measured by the expressions of peroxisome proliferator-activated receptor-γ (PPARγ), PPARγcoactivator 1α (PGC-1α), uncoupling protein 1 (UCP-1), the second messenger cyclic guanosine-3', 5'-monophosphate (cGMP),PR domain containing 16 zinc finger transcription factor (Prdm16) and deiodinase, iodothyronine, type II (DIO2).The metabolic makers will be measured by blood pressure, heart rate, thyroid functions, resting metabolic rate, respiratory quotient, blood cGMP, blood insulin and blood glucose.

Eligibility Criteria:
Inclusion Criteria:

* overweight volunteers
* 20-30 years old
* body mass index \>=25 kg/m2
* normal glucose tolerance

Exclusion Criteria:

* normal body mass index
* abnormal cardiovascular status
* women
* history of any local or systemic infectious disease with fever or requiring antibiotic within four weeks of drug administration
* current addiction to alcohol or substances of abuse
* children
* current addiction to alcohol or substances of abuse
* mental incapacity
* the use of any medication within four weeks
* subjects with hyperthyroidism or hypothyroidism, hypertension (even if controlled with medications)