C/EBP Regulates Hepatic Transcription of 11β-Hydroxysteroid Dehydrogenase Type 1

Williams, Louise; Lyons, V.; Macleod, I R; Rajan, Vidya; Darlington, Gretchen J.; Poli, Valeria; Seckl, Jonathan R.; Chapman, Karen

doi:10.1074/jbc.m001286200

Cited by 104 publications

(38 citation statements)

References 51 publications

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“…Both the increased 11␤-HSD1 expression and late induction are in agreement with previous results examining 11␤-HSD1 mRNA expression during 3T3-L1 adipogenesis (33). Additionally, the timing of increased C/EBP␣ levels preceding 11␤-HSD1 up-regulation suggested that this transcription factor may control 11␤-HSD1 expression, as has been reported in liver cells (34). However, additional experiments would be required to prove a causal link.…”

Section: Dehydrocorticosterone Promotes 3t3-l1 Differentiation-supporting

confidence: 80%

Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11β-Hydroxysteroid Dehydrogenase-1 Levels

Kim¹,

Temple²,

Jones

et al. 2007

Journal of Biological Chemistry

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The localized activation of circulating glucocorticoids in vivo by the enzyme 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD1) plays a critical role in the development of the metabolic syndrome. However, the precise contribution of 11␤-HSD1 in the initiation of adipogenesis by inactive glucocorticoids is not fully understood. 3T3-L1 fibroblasts can be terminally differentiated to mature adipocytes in a glucocorticoid-dependent manner. Both inactive rodent dehydrocorticosterone and human cortisone were able to substitute for the synthetic glucocorticoid dexamethasone in 3T3-L1 adipogenesis, suggesting a potential role for 11␤-HSD1 in these effects. Differentiation of 3T3-L1 cells caused a strong increase in 11␤-HSD1 protein levels, which occurred late in the differentiation protocol. Reduction of 11␤-HSD1 activity in 3T3-L1 fibroblasts, achieved by pharmacological inhibition or adenovirally mediated delivery of short hairpin RNA constructs, specifically blocked the ability of inactive glucocorticoids to drive 3T3-L1 differentiation. However, even modest increases in exogenous 11␤-HSD1 expression in 3T3-L1 fibroblasts, to levels comparable with endogenous 11␤-HSD1 in differentiated 3T3-L1 adipocytes, were sufficient to block adipogenesis. Luciferase reporter assays indicated that overexpressed 11␤-HSD1 was catalyzing the inactivating dehydrogenase reaction, because the ability of both active and inactive glucocorticoids to activate the glucocorticoid receptor were largely suppressed. These results suggest that the temporal regulation of 11␤-HSD1 expression is tightly controlled in 3T3-L1 cells, so as to mediate the initiation of differentiation by inactive glucocorticoids and also to prevent the inhibitory activity of prematurely expressed 11␤-HSD1 during adipogenesis.

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Section: Dehydrocorticosterone Promotes 3t3-l1 Differentiation-supporting

confidence: 80%

Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11β-Hydroxysteroid Dehydrogenase-1 Levels

Kim¹,

Temple²,

Jones

et al. 2007

Journal of Biological Chemistry

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“…CCAAT/enhancer-binding protein α (C/EBPα) has been shown to be a potent activator of the basal transcription of 11β-HSD1 whereas CCAAT/enhancer-binding protein β (C/EBPβ) is only a weak activator and competing with the strong activation of 11β-HSD1 promoter activity mediated by C/EBPα [30], [31], therefore, the transcriptional activity of 11β-HSD1 was assessed by the ratio of C/EBPα to C/EBPβ rather than measuring a single transcription factor alone. In retroperitoneal adipose tissue, the ratio of C/EBPα to C/EBPβ increased with postnatal age and peaked at W6 in SL ( P <0.05) and NL ( P <0.05) rats respectively.…”

Section: Resultsmentioning

confidence: 99%

Neonatal Overfeeding Induced by Small Litter Rearing Causes Altered Glucocorticoid Metabolism in Rats

et al. 2011

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Elevated glucocorticoid (GC) activity may be involved in the development of the metabolic syndrome. Tissue GC exposure is determined by the tissue-specific GC-activating enzyme 11β-hydroxysteriod dehydrogenase type 1 (11β-HSD1) and the GC-inactivating enzyme 5α-reductase type 1 (5αR1), as well as 5β-reductase (5βR). Our aim was to study the effects of neonatal overfeeding induced by small litter rearing on the expression of GC-regulating enzymes in adipose tissue and/or liver and on obesity-related metabolic disturbances during development. Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litters, SL) or ten (normal litters, NL) on postnatal day 3 and then given standard chow from postnatal week 3 onward (W3). Small litter rearing induced obesity, hyperinsulinemia, and higher circulating corticosterone in adults. 11β-HSD1 expression and enzyme activity in retroperitoneal, but not in epididymal, adipose tissue increased with postnatal time and peaked at W5/W6 in both groups before declining. From W8, 11β-HSD1 expression and enzyme activity levels in retroperitoneal fat persisted at significantly higher levels in SL compared to NL rats. Hepatic 11β-HSD1 enzyme activity in SL rats was elevated from W3 to W16 compared to NL rats. Hepatic 5αR1 and 5βR expression was higher in SL compared to NL rats after weaning until W6, whereupon expression decreased in the SL rats and remained similar to that in NL rats. In conclusion, small litter rearing in rats induced peripheral tissue-specific alterations in 11β-HSD1 expression and activity and 5αR1 and 5βR expression during puberty, which could contribute to elevated tissue-specific GC exposure and aggravate the development of metabolic dysregulation in adults.

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“…Differences in the activity of CCAAT/enhancer-binding proteins (C/EBPs), which are required for adipocytes differentiation and maturation, between liver and adipose tissue could be involved. It has been shown that in liver, C/EBP␣ is a potent activator of the 11␤-HSD-1 gene, whereas C/EBP␤ acts as a dominant repressor of C/EBP␣-stimulated 11␤-HSD-1 promoter activity (46). Conversely, although both C/EBP␣ and -␤ are required for the basal transcriptional activity of 11␤-HSD-1 in 3T3-L1, a preadipocyte cell line, C/EBP␤ is strongly involved in forskolin-induced stimulation of 11␤-HSD-1 gene transcription (47).…”

Section: Discussionmentioning

confidence: 99%

Postnatal Programming of Glucocorticoid Metabolism in Rats Modulates High-Fat Diet–Induced Regulation of Visceral Adipose Tissue Glucocorticoid Exposure and Sensitivity and Adiponectin and Proinflammatory Adipokines Gene Expression in Adulthood

et al. 2008

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OBJECTIVE-Alterations of the perinatal environment, which lead to increased prevalence of the metabolic syndrome in adulthood, program an upregulation of systemic and/or adipose tissue glucocorticoid metabolism (11␤-hydroxysteroid dehydrogenase type 1 [11␤-HSD-1]-induced corticosterone reactivation). We hypothesized that postnatal programming could modulate high-fat diet-induced adipose tissue dysregulation in adulthood. RESEARCH DESIGN AND METHODS-We compared the effects of chronic (since weaning) high-or low-fat diet in postnatally normofed (control) or overfed (programmed) rats. RESULTS-Postnatal programming accentuated high-fat dietinduced overweight, insulin resistance, glucose intolerance, and decrease in circulating and epididymal adipose tissue adiponectin. Neither manipulation altered liver function. Postnatal programming or high-fat diet increased systemic corticosterone production, which was not further modified when both manipulations were associated. Postnatal programming suppressed high-fat diet-induced decrease in mesenteric adipose tissue (MAT) glucocorticoid sensitivity and triggered high-fat dietinduced increase in MAT glucocorticoid exposure, subsequent to enhanced MAT 11␤-HSD-1 gene expression. MAT tumor necrosis factor (TNF)-␣, TNF-receptor 1, interleukin (IL)-6, resistin, and plasminogen activator inhibitor-1 mRNAs were not changed by high-fat feeding in control rats and showed a large increase in programmed animals, with this effect further enhanced by highfat diet for TNF-␣ and IL-6. CONCLUSIONS-Our data show for the first time that postnatal manipulation programs high-fat diet-induced upregulation of MAT glucocorticoid exposure, sensitivity, and inflammatory status and therefore reveal the pivotal role of the environment during the perinatal period on the development of diet-induced adipose tissue dysregulation in adulthood. They also urge the need for clinical trials with specific 11␤-HSD-1 inhibitors. Diabetes 57:669-677, 2008

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C/EBP Regulates Hepatic Transcription of 11β-Hydroxysteroid Dehydrogenase Type 1

Cited by 104 publications

References 51 publications

Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11β-Hydroxysteroid Dehydrogenase-1 Levels

Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11β-Hydroxysteroid Dehydrogenase-1 Levels

Neonatal Overfeeding Induced by Small Litter Rearing Causes Altered Glucocorticoid Metabolism in Rats

Postnatal Programming of Glucocorticoid Metabolism in Rats Modulates High-Fat Diet–Induced Regulation of Visceral Adipose Tissue Glucocorticoid Exposure and Sensitivity and Adiponectin and Proinflammatory Adipokines Gene Expression in Adulthood

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