Cargando…
11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192288/ https://www.ncbi.nlm.nih.gov/pubmed/24169553 http://dx.doi.org/10.1210/en.2013-1613 |
_version_ | 1782338750583406592 |
---|---|
author | Harno, Erika Cottrell, Elizabeth C. Yu, Alice DeSchoolmeester, Joanne Gutierrez, Pablo Morentin Denn, Mark Swales, John G. Goldberg, Fred W. Bohlooly-Y, Mohammad Andersén, Harriet Wild, Martin J. Turnbull, Andrew V. Leighton, Brendan White, Anne |
author_facet | Harno, Erika Cottrell, Elizabeth C. Yu, Alice DeSchoolmeester, Joanne Gutierrez, Pablo Morentin Denn, Mark Swales, John G. Goldberg, Fred W. Bohlooly-Y, Mohammad Andersén, Harriet Wild, Martin J. Turnbull, Andrew V. Leighton, Brendan White, Anne |
author_sort | Harno, Erika |
collection | PubMed |
description | The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)–fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting “off-target” mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1–independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a “step-change” treatment for diabetes and/or obesity. |
format | Online Article Text |
id | pubmed-4192288 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-41922882014-10-27 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms Harno, Erika Cottrell, Elizabeth C. Yu, Alice DeSchoolmeester, Joanne Gutierrez, Pablo Morentin Denn, Mark Swales, John G. Goldberg, Fred W. Bohlooly-Y, Mohammad Andersén, Harriet Wild, Martin J. Turnbull, Andrew V. Leighton, Brendan White, Anne Endocrinology Energy Balance-Obesity The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)–fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting “off-target” mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1–independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a “step-change” treatment for diabetes and/or obesity. Endocrine Society 2013-12 2013-10-29 /pmc/articles/PMC4192288/ /pubmed/24169553 http://dx.doi.org/10.1210/en.2013-1613 Text en Copyright © 2013 by The Endocrine Society This article has been published under the terms of the Creative Commons Attribution License (CC-BY (http://creativecommons.org/licenses/by/3.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the Endocrine Society the exclusive right to publish the article and identify itself as the original publisher. |
spellingShingle | Energy Balance-Obesity Harno, Erika Cottrell, Elizabeth C. Yu, Alice DeSchoolmeester, Joanne Gutierrez, Pablo Morentin Denn, Mark Swales, John G. Goldberg, Fred W. Bohlooly-Y, Mohammad Andersén, Harriet Wild, Martin J. Turnbull, Andrew V. Leighton, Brendan White, Anne 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms |
title | 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms |
title_full | 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms |
title_fullStr | 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms |
title_full_unstemmed | 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms |
title_short | 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms |
title_sort | 11β-hydroxysteroid dehydrogenase type 1 (11β-hsd1) inhibitors still improve metabolic phenotype in male 11β-hsd1 knockout mice suggesting off-target mechanisms |
topic | Energy Balance-Obesity |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192288/ https://www.ncbi.nlm.nih.gov/pubmed/24169553 http://dx.doi.org/10.1210/en.2013-1613 |
work_keys_str_mv | AT harnoerika 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT cottrellelizabethc 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT yualice 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT deschoolmeesterjoanne 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT gutierrezpablomorentin 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT dennmark 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT swalesjohng 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT goldbergfredw 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT bohloolyymohammad 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT andersenharriet 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT wildmartinj 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT turnbullandrewv 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT leightonbrendan 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms AT whiteanne 11bhydroxysteroiddehydrogenasetype111bhsd1inhibitorsstillimprovemetabolicphenotypeinmale11bhsd1knockoutmicesuggestingofftargetmechanisms |