scholarly journals Peroxisome Proliferator-activated Receptor-γ Ligands Inhibit Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity

2001 ◽  
Vol 276 (16) ◽  
pp. 12629-12635 ◽  
Author(s):  
Joel Berger ◽  
Michael Tanen ◽  
Alex Elbrecht ◽  
Anne Hermanowski-Vosatka ◽  
David E. Moller ◽  
...  
Keyword(s):  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression And Activity

scholarly journals Effects of Peroxisome Proliferator-Activated Receptor-α and -γ Agonists on 11β-Hydroxysteroid Dehydrogenase Type 1 in Subcutaneous Adipose Tissue in Men

2007 ◽  
Vol 92 (5) ◽  
pp. 1848-1856 ◽  
Author(s):  
Deborah J. Wake ◽  
Roland H. Stimson ◽  
Garry D. Tan ◽  
Natalie Z. M. Homer ◽  
Ruth Andrew ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Plasma Cortisol ◽  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Cortisol Secretion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Healthy Men ◽  
Pparγ Agonists

Abstract Context: In animals, peroxisome proliferator-activated receptor-α (PPARα) and PPARγ agonists down-regulate 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mRNA and activity in liver and adipose tissue, respectively, and PPARγ agonists reduce ACTH secretion from corticotrope cells. Objective: Our objective was to test whether PPAR agonists alter cortisol secretion and peripheral regeneration by 11β-HSD1 in humans and whether reduced cortisol action contributes to metabolic effects of PPARγ 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 PPARα agonist (fenofibrate) or PPARγ agonist (rosiglitazone) had no effect on cortisol secretion, hepatic cortisol generation after oral cortisone administration, or tracer kinetics during 9,11,12,12-[2H]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 11β-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 11β-HSD1 mRNA in sc adipose tissue but increased plasma cortisol concentrations. Conclusions: Neither PPARα nor PPARγ agonists down-regulate 11β-HSD1 or cortisol secretion acutely in humans. The early insulin-sensitizing effect of rosiglitazone is not dependent on reducing intracellular glucocorticoid concentrations. Reduced adipose 11β-HSD1 expression and increased plasma cortisol during longer therapy with rosiglitazone probably reflect indirect effects, e.g. mediated by changes in body fat.

Maternal restraint stress during pregnancy in mice induces 11β-HSD1-associated metabolic changes in the livers of the offspring

2015 ◽  
Vol 6 (2) ◽  
pp. 105-114 ◽  
Author(s):  
H. Maeyama ◽  
T. Hirasawa ◽  
Y. Tahara ◽  
C. Obata ◽  
H. Kasai ◽  
...  
Keyword(s):  
Restraint Stress ◽  
Active Form ◽  
Hydroxysteroid Dehydrogenase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Systems ◽  
Central Nervous Systems ◽  
Pregnant Mice ◽  
Related Proteins

In rats, maternal exposure to restraint stress during pregnancy can induce abnormalities in the cardiovascular and central nervous systems of the offspring. These effects are mediated by long-lasting hyperactivation of the hypothalamic–pituitary–adrenal axis. However, little is known about the potential effects of stress during pregnancy on metabolic systems. We examined the effect of restraint stress in pregnant mice on the liver function of their offspring. The offspring of stressed mothers showed significantly higher lipid accumulation in the liver after weaning than did the controls; this accumulation was associated with increased expression of lipid metabolism-related proteins such as alanine aminotransferase 2 diglyceride acyltransferase 1, peroxisome proliferator-activated receptor gamma and glucocorticoid receptor. Additionally, we observed increased levels of 11β-hydroxysteroid dehydrogenase type 1, an intercellular mediator that converts glucocorticoid from the inactive to the active form, in the foetal and postnatal periods. These results indicate that restraint stress in pregnancy in mice induces metabolic abnormalities via 11β-hydroxysteroid dehydrogenase type 1-related pathways in the foetal liver. It is therefore possible that exposure to stress in pregnant women may be a risk factor for metabolic syndromes (e.g. fatty liver) in children.

scholarly journals Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates

2005 ◽  
Vol 389 (3) ◽  
pp. 913-918 ◽  
Author(s):  
Julio Sevillano ◽  
Inmaculada C. López-Pérez ◽  
Emilio Herrera ◽  
María del Pilar Ramos ◽  
Carlos Bocos
Keyword(s):  
Body Mass ◽  
Control Cell ◽  
Late Pregnancy ◽  
Tissue Growth ◽  
Peroxisome Proliferator ◽  
Pregnant Rats ◽  
Peroxisome Proliferator Activated Receptor ◽  
Akt Phosphorylation ◽  
Insulin Resistant

The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARγ (peroxisome-proliferator-activated receptor γ) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified (‘free’) fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARγ ligands and by hyperinsulinaemia as being responsible for a major insulin-resistant condition.

scholarly journals Activation of Peroxisome Proliferator-activated Receptor α (PPARα) Suppresses Hypoxia-inducible Factor-1α (HIF-1α) Signaling in Cancer Cells

2012 ◽  
Vol 287 (42) ◽  
pp. 35161-35169 ◽  
Author(s):  
Jundong Zhou ◽  
Shuyu Zhang ◽  
Jing Xue ◽  
Jori Avery ◽  
Jinchang Wu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Hypoxia Inducible Factor ◽  
Proteasome Inhibitors ◽  
Tube Formation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hypoxia Inducible Factor 1Α ◽  
Anticancer Properties ◽  
Pparγ Agonist ◽  
Expression And Activity

Activation of peroxisome proliferator-activated receptor α (PPARα) has been demonstrated to inhibit tumor growth and angiogenesis, yet the mechanisms behind these actions remain to be characterized. In this study, we examined the effects of PPARα activation on the hypoxia-inducible factor-1α (HIF-1α) signaling pathway in human breast (MCF-7) and ovarian (A2780) cancer cells under hypoxia. Incubation of cancer cells under 1% oxygen for 16 h significantly induced HIF-1α expression and activity as assayed by Western blotting and reporter gene analysis. Treatment of the cells with PPARα agonists, but not a PPARγ agonist, prior to hypoxia diminished hypoxia-induced HIF-1α expression and activity, and addition of a PPARα antagonist attenuated the suppression of HIF-1α signaling. Activation of PPARα attenuated hypoxia-induced HA-tagged HIF-1α protein expression without affecting the HA-tagged HIF-1α mutant protein level, indicating that PPARα activation promotes HIF-1α degradation in these cells. This was further confirmed using proteasome inhibitors, which reversed PPARα-mediated suppression of HIF-1α expression under hypoxia. Using the co-immunoprecipitation technique, we found that activation of PPARα enhances the binding of HIF-1α to von Hippel-Lindau tumor suppressor (pVHL), a protein known to mediate HIF-1α degradation through the ubiquitin-proteasome pathway. Following PPARα-mediated suppression of HIF-1α signaling, VEGF secretion from the cancer cells was significantly reduced, and tube formation by endothelial cells was dramatically impaired. Taken together, these findings demonstrate for the first time that activation of PPARα suppresses hypoxia-induced HIF-1α signaling in cancer cells, providing novel insight into the anticancer properties of PPARα agonists.

Control of pain initiation by endogenous cannabinoids

2018 ◽  
Author(s):  
Andrea G. Hohmann
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peripheral Mechanism ◽  
Antinociceptive Effects ◽  
The Central Nervous System ◽  
Cns Side Effects ◽  
Endogenous Cannabinoids ◽  
Redundant Functions

The landmark paper discussed in this chapter, published by Calignano et al. in 1998, focuses on the control of pain initiation by endogenous cannabinoids. In the paper, analgesic lipid mediators are shown to be present in peripheral paw tissue where they control the ability of pain signals to ascend to the central nervous system (CNS). Anandamide acts through a peripheral mechanism to suppress inflammatory pain via cannabinoid type 1 receptors. Palmitoylethanolamine, subsequently identified as an endogenous ligand for peroxisome proliferator-activated receptor-α‎, produces peripheral antinociceptive effects via a mechanism similar to that for the cannabinoid type 2 receptor. These lipids do not serve redundant functions and, in combination, produce synergistic antinociceptive effects. These observations suggested that drug-development efforts targeting peripheral control of pain may elucidate improved pharmacotherapies that lack the unwanted CNS side effects of current treatments.

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