Effects of peroxisome proliferator-activated receptor-alpha and -gamma agonists on 11beta-hydroxysteroid dehydrogenase type 1 in subcutaneous adipose tissue in men.

Abstract

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.

• Authors: Deborah J Wake, Roland H Stimson, Garry D Tan, Natalie Z M Homer, Ruth Andrew, Fredrik Karpe, Brian R Walker
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 92 Issue 5 Pg. 1848-56 (May 2007) ISSN: 0021-972X [Print] United States
• PMID: 17327378 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Hormone Antagonists
• Hypolipidemic Agents
• PPAR alpha
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• Mifepristone
• 11-beta-Hydroxysteroid Dehydrogenase Type 1
• Fenofibrate
• Cortisone
• Hydrocortisone
• Metyrapone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (metabolism)
• Adult
• Aged
• Cortisone (pharmacokinetics)
• Cross-Over Studies
• Double-Blind Method
• Enzyme Inhibitors (pharmacology)
• Fenofibrate (therapeutic use)
• Gas Chromatography-Mass Spectrometry
• Hormone Antagonists (pharmacology)
• Humans
• Hydrocortisone (blood, urine)
• Hypolipidemic Agents (therapeutic use)
• Insulin Resistance (physiology)
• Kinetics
• Liver (drug effects, enzymology, metabolism)
• Male
• Metyrapone (pharmacology)
• Microdialysis
• Middle Aged
• Mifepristone (pharmacology)
• Obesity (enzymology)
• PPAR alpha (agonists)
• PPAR gamma (agonists)
• Rosiglitazone
• Subcutaneous Fat (drug effects, enzymology)
• Thiazolidinediones (therapeutic use)