title: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors still improve metabolic phenotype in male 11β-HSD1 knockout mice suggesting off-target mechanisms.
abstract: 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.
authors.affiliation: Faculty of Life Sciences and Faculty of Medical and Human Sciences, AV Hill Building, University of Manchester, Manchester, M13 9PT, United Kingdom. awhite@manchester.ac.uk.
authors.forename: Erika
authors.initials: E
authors.lastname: Harno
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Cottrell
authors.forename: Alice
authors.initials: A
authors.lastname: Yu
authors.forename: Joanne
authors.initials: J
authors.lastname: DeSchoolmeester
authors.forename: Pablo Morentin
authors.initials: PM
authors.lastname: Gutierrez
authors.forename: Mark
authors.initials: M
authors.lastname: Denn
authors.forename: John G
authors.initials: JG
authors.lastname: Swales
authors.forename: Fred W
authors.initials: FW
authors.lastname: Goldberg
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.forename: Harriet
authors.initials: H
authors.lastname: Andersén
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Wild
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: Brendan
authors.initials: B
authors.lastname: Leighton
authors.forename: Anne
authors.initials: A
authors.lastname: White
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D001835:Body Weight; D001921:Brain / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; C585925:MK-0916; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D014230:Triazoles; C516138:dorsomorphin; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose