Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism
Lizhi Fu,1 Fenfen Li,1 Antje Bruckbauer,2 Qiang Cao,1 Xin Cui,1 Rui Wu,1 Hang Shi,1 Bingzhong Xue,1 Michael B Zemel21Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, 2NuSirt Biopharma Inc., Nashville, TN, USA Purpose: Leucine activates SIRT1/AMP-activated p...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Dove Medical Press
2015-05-01
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| Series: | Diabetes, Metabolic Syndrome and Obesity |
| Online Access: | http://www.dovepress.com/interaction-between-leucine-and-phosphodiesterase-5-inhibition-in-modu-peer-reviewed-article-DMSO |
| _version_ | 1797935150958379008 |
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| author | Fu L Li F Bruckbauer A Cao Q Cui X Wu R Shi H Xue B Zemel MB |
| author_facet | Fu L Li F Bruckbauer A Cao Q Cui X Wu R Shi H Xue B Zemel MB |
| author_sort | Fu L |
| collection | DOAJ |
| description | Lizhi Fu,1 Fenfen Li,1 Antje Bruckbauer,2 Qiang Cao,1 Xin Cui,1 Rui Wu,1 Hang Shi,1 Bingzhong Xue,1 Michael B Zemel21Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, 2NuSirt Biopharma Inc., Nashville, TN, USA Purpose: 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. Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine–PDE5 inhibitor combinations. Keywords: AMPK, diabetes, icariin, PDE5, sildenafil, SIRT1, steatosis |
| first_indexed | 2024-04-10T18:10:59Z |
| format | Article |
| id | doaj.art-ee87c9ea13064cacbd8a326c3eb4d5c6 |
| institution | Directory Open Access Journal |
| issn | 1178-7007 |
| language | English |
| last_indexed | 2024-04-10T18:10:59Z |
| publishDate | 2015-05-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Diabetes, Metabolic Syndrome and Obesity |
| spelling | doaj.art-ee87c9ea13064cacbd8a326c3eb4d5c62023-02-02T11:19:43ZengDove Medical PressDiabetes, Metabolic Syndrome and Obesity1178-70072015-05-012015default22723921621Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolismFu LLi FBruckbauer ACao QCui XWu RShi HXue BZemel MBLizhi Fu,1 Fenfen Li,1 Antje Bruckbauer,2 Qiang Cao,1 Xin Cui,1 Rui Wu,1 Hang Shi,1 Bingzhong Xue,1 Michael B Zemel21Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, 2NuSirt Biopharma Inc., Nashville, TN, USA Purpose: 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. Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine–PDE5 inhibitor combinations. Keywords: AMPK, diabetes, icariin, PDE5, sildenafil, SIRT1, steatosis http://www.dovepress.com/interaction-between-leucine-and-phosphodiesterase-5-inhibition-in-modu-peer-reviewed-article-DMSO |
| spellingShingle | Fu L Li F Bruckbauer A Cao Q Cui X Wu R Shi H Xue B Zemel MB Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism Diabetes, Metabolic Syndrome and Obesity |
| title | Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism |
| title_full | Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism |
| title_fullStr | Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism |
| title_full_unstemmed | Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism |
| title_short | Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism |
| title_sort | interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism |
| url | http://www.dovepress.com/interaction-between-leucine-and-phosphodiesterase-5-inhibition-in-modu-peer-reviewed-article-DMSO |
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