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A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits
BACKGROUND: 11ß–hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HS...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127523/ https://www.ncbi.nlm.nih.gov/pubmed/25098735 http://dx.doi.org/10.1186/2050-6511-15-43 |
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author | Anil, Tharappel M Dandu, Anilkumar Harsha, KrishnaReddy Singh, Jaideep Shree, Nitya Kumar, Venkatesh Satish Lakshmi, Mudigere N Sunil, Venkategowda Harish, Chandrashekaran Balamurali, Gundalmandikal V Naveen Kumar, Baisani S Gopala, Aralakuppe S Pratibha, Shivakumar Sadasivuni, ManojKumar Anup, Mammen O Moolemath, Yoganand Venkataranganna, Marikunte V Jagannath, Madanahalli R Somesh, Baggavalli P |
author_facet | Anil, Tharappel M Dandu, Anilkumar Harsha, KrishnaReddy Singh, Jaideep Shree, Nitya Kumar, Venkatesh Satish Lakshmi, Mudigere N Sunil, Venkategowda Harish, Chandrashekaran Balamurali, Gundalmandikal V Naveen Kumar, Baisani S Gopala, Aralakuppe S Pratibha, Shivakumar Sadasivuni, ManojKumar Anup, Mammen O Moolemath, Yoganand Venkataranganna, Marikunte V Jagannath, Madanahalli R Somesh, Baggavalli P |
author_sort | Anil, Tharappel M |
collection | PubMed |
description | BACKGROUND: 11ß–hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and ‘pan tissue’ acting 11β-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome. METHODS: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively. RESULTS: CNX-010-49 a highly potent and selective pan tissue acting 11β-HSD1 inhibitor (EC(50) = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits. CONCLUSIONS: These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes. |
format | Online Article Text |
id | pubmed-4127523 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-41275232014-08-12 A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits Anil, Tharappel M Dandu, Anilkumar Harsha, KrishnaReddy Singh, Jaideep Shree, Nitya Kumar, Venkatesh Satish Lakshmi, Mudigere N Sunil, Venkategowda Harish, Chandrashekaran Balamurali, Gundalmandikal V Naveen Kumar, Baisani S Gopala, Aralakuppe S Pratibha, Shivakumar Sadasivuni, ManojKumar Anup, Mammen O Moolemath, Yoganand Venkataranganna, Marikunte V Jagannath, Madanahalli R Somesh, Baggavalli P BMC Pharmacol Toxicol Research Article BACKGROUND: 11ß–hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and ‘pan tissue’ acting 11β-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome. METHODS: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively. RESULTS: CNX-010-49 a highly potent and selective pan tissue acting 11β-HSD1 inhibitor (EC(50) = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits. CONCLUSIONS: These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes. BioMed Central 2014-08-07 /pmc/articles/PMC4127523/ /pubmed/25098735 http://dx.doi.org/10.1186/2050-6511-15-43 Text en Copyright © 2014 Anil et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Anil, Tharappel M Dandu, Anilkumar Harsha, KrishnaReddy Singh, Jaideep Shree, Nitya Kumar, Venkatesh Satish Lakshmi, Mudigere N Sunil, Venkategowda Harish, Chandrashekaran Balamurali, Gundalmandikal V Naveen Kumar, Baisani S Gopala, Aralakuppe S Pratibha, Shivakumar Sadasivuni, ManojKumar Anup, Mammen O Moolemath, Yoganand Venkataranganna, Marikunte V Jagannath, Madanahalli R Somesh, Baggavalli P A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits |
title | A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits |
title_full | A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits |
title_fullStr | A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits |
title_full_unstemmed | A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits |
title_short | A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits |
title_sort | novel 11β-hydroxysteroid dehydrogenase type1 inhibitor cnx-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese c57b6/j mice with a potential to provide cardio protective benefits |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127523/ https://www.ncbi.nlm.nih.gov/pubmed/25098735 http://dx.doi.org/10.1186/2050-6511-15-43 |
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