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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Fu L, Li F, Bruckbauer A, Cao Q, Cui X, Wu R, Shi H, Xue B, Zemel MB
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2015
Materias:	Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/ee87c9ea13064cacbd8a326c3eb4d5c6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ee87c9ea13064cacbd8a326c3eb4d5c6
record_format	dspace
spelling	oai:doaj.org-article:ee87c9ea13064cacbd8a326c3eb4d5c62021-12-02T07:21:12ZInteraction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism1178-7007https://doaj.org/article/ee87c9ea13064cacbd8a326c3eb4d5c62015-05-01T00:00:00Zhttp://www.dovepress.com/interaction-between-leucine-and-phosphodiesterase-5-inhibition-in-modu-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Lizhi 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 Fu LLi FBruckbauer ACao QCui XWu RShi HXue BZemel MBDove Medical PressarticleSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol 2015, Iss default, Pp 227-239 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Specialties of internal medicine RC581-951
spellingShingle	Specialties of internal medicine RC581-951 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
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
format	article
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
title	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_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_sort	interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism
publisher	Dove Medical Press
publishDate	2015
url	https://doaj.org/article/ee87c9ea13064cacbd8a326c3eb4d5c6
work_keys_str_mv	AT ful interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT lif interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT bruckbauera interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT caoq interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT cuix interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT wur interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT shih interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT xueb interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism AT zemelmb interactionbetweenleucineandphosphodiesterase5inhibitioninmodulatinginsulinsensitivityandlipidmetabolism
_version_	1718399491141271552

Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism

Ejemplares similares