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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...

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Autores principales: 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
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
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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.
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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
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