title: Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism.
abstract: OBJECTIVE
  Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide-cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects.
  
  
  METHODS
  We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice.
  
  
  RESULTS
  Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1-10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P<0.002), insulin (37%, P<0.05), area under the glucose tolerance curve (20%, P<0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis.
  
  
  CONCLUSIONS
  These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine-PDE5 inhibitor combinations.
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Li
authors.affiliation: NuSirt Biopharma Inc., Nashville, TN, USA.
authors.forename: Antje
authors.initials: A
authors.lastname: Bruckbauer
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA.
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.affiliation: NuSirt Biopharma Inc., Nashville, TN, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Zemel
keywords: AMPK; PDE5; SIRT1; diabetes; icariin; sildenafil; steatosis