Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.
CONTEXT: In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope...
| Main Authors: | , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2007
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| _version_ | 1797082348849725440 |
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| author | Wake, D Stimson, R Tan, G Homer, N Andrew, R Karpe, F Walker, B |
| author_facet | Wake, D Stimson, R Tan, G Homer, N Andrew, R Karpe, F Walker, B |
| author_sort | Wake, D |
| collection | OXFORD |
| description | CONTEXT: In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. OBJECTIVE: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. DESIGN AND SETTING: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. PATIENTS AND PARTICIPANTS: Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. CONCLUSIONS: Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat. |
| first_indexed | 2024-03-07T01:26:55Z |
| format | Journal article |
| id | oxford-uuid:924c0f64-bf96-4f43-9185-6cd2c3a7261a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:26:55Z |
| publishDate | 2007 |
| record_format | dspace |
| spelling | oxford-uuid:924c0f64-bf96-4f43-9185-6cd2c3a7261a2022-03-26T23:24:25ZEffects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:924c0f64-bf96-4f43-9185-6cd2c3a7261aEnglishSymplectic Elements at Oxford2007Wake, DStimson, RTan, GHomer, NAndrew, RKarpe, FWalker, B CONTEXT: In animals, peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma agonists down-regulate 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARgamma agonists reduce ACTH secretion from corticotrope cells. OBJECTIVE: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11beta-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARgamma agonists. DESIGN AND SETTING: Three randomized placebo-controlled crossover studies were conducted at a clinical research facility. PATIENTS AND PARTICIPANTS: Healthy men and patients with type 2 diabetes participated. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: In nine healthy men, 7 d of PPARalpha agonist (fenofibrate) or PPARgamma agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[(2)H](4)-cortisol infusion, although rosiglitazone marginally reduced cortisol generation in sc adipose tissue measured by in vivo microdialysis. In 12 healthy men, 4-5 wk of rosiglitazone increased insulin sensitivity during insulin infusion but did not change 11beta-HSD1 mRNA or activity in sc adipose tissue, and insulin sensitization was unaffected by glucocorticoid blockade with a combination of metyrapone and RU38486. In 12 men with type 2 diabetes 12 wk of rosiglitazone reduced arteriovenous cortisone extraction across abdominal sc adipose tissue and reduced 11beta-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. CONCLUSIONS: Neither PPARalpha nor PPARgamma agonists down-regulate 11beta-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11beta-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat. |
| spellingShingle | Wake, D Stimson, R Tan, G Homer, N Andrew, R Karpe, F Walker, B Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. |
| title | Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. |
| title_full | Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. |
| title_fullStr | Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. |
| title_full_unstemmed | Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. |
| title_short | Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men. |
| title_sort | effects of peroxisome proliferator activated receptor alpha and gamma agonists on 11beta hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men |
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