Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women

Blouin, Karine; Blanchette, S.; Richard, Christian; Dupont, Pierre; Luu‐The, Van; Tchernof, André

doi:10.1152/ajpendo.00312.2004

Cited by 55 publications

(44 citation statements)

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“…Induction of fat cell differentiation led to a significant increase in the production of 20␣-reduced progesterone but not other metabolites (28). Moreover, we have shown that 20␣-reductase activity and expression of AKR1C isoforms in omental adipose tissue are positively associated with visceral fat accumulation (2). In the present study, we confirm that progesterone inactivation through 20␣-HSD activity is mediated mainly by AKR1C1.…”

Section: Discussionsupporting

confidence: 82%

Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes

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Côté

Blouin

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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-The, Tchernof A. Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes. Am J Physiol Endocrinol Metab 302: E941-E949, 2012. First published January 24, 2012; doi:10.1152/ajpendo.00069.2011.-Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3␣-diol is stimulated by glucocorticoids in human preadipocytes. We sought to characterize glucocorticoid-induced androgen inactivation in human preadipocytes and to establish its role in the antiadipogenic action of DHT. Subcutaneous and omental primary preadipocyte cultures were established from fat samples obtained in subjects undergoing abdominal surgeries. Inactivation of DHT to 3␣/␤-diol for 24 h was measured in dexamethasone-or vehicle-treated cells. Specific downregulation of aldo-keto reductase 1C (AKR1C) enzymes in human preadipocytes was achieved using RNA interference. In whole adipose tissue sample, cortisol production was positively correlated with androgen inactivation in both subcutaneous and omental adipose tissue (P Ͻ 0.05). Maximal dexamethasone (1 M) stimulation of DHT inactivation was higher in omental compared with subcutaneous fat from men as well as subcutaneous and omental fat from women (P Ͻ 0.05). A significant positive correlation was observed between BMI and maximal dexamethasone-induced DHT inactivation rates in subcutaneous and omental adipose tissue of men and women (r ϭ 0.24, n ϭ 26, P Ͻ 0.01). siRNA-induced downregulation of AKR1C2, but not AKR1C1 or AKR1C3, significantly reduced basal and glucocorticoid-induced androgen inactivation rates (P Ͻ 0.05). The inhibitory action of DHT on preadipocyte differentiation was potentiated following AKR1C2 but not AKR1C1 or AKR1C3 downregulation. Specifically, lipid accumulation, G3PDH activity, and FABP4 mRNA expression in differentiated preadipocytes exposed to DHT were reduced further upon AKR1C2 siRNA transfection. We conclude that glucocorticoid-induced androgen inactivation is mediated by AKR1C2 and is particularly effective in omental preadipocytes of obese men. The interplay between glucocorticoids and AKR1C2-dependent androgen inactivation may locally modulate adipogenesis and lipid accumulation in a depot-specific manner.3␣-hydroxysteroid dehydrogenase; 5␣-dihydrotestosterone; dexamethasone THE PROPENSITY TO ACCUMULATE LIPIDS in the visceral rather than in the subcutaneous adipose tissue compartment is associated with metabolic disorders. Little is known about the factors leading to preferential visceral fat accumulation when facing excess energy intake, but steroid hormones such as glucocorticoids and androgens appear to play a key role.

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Section: Discussionsupporting

confidence: 82%

Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes

Veilleux

Côté

Blouin

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…We have observed correlations between AKR1C2 protein level in adipose tissue and parameters of adiposity ). It has also been reported that the level of AKR1C2 mRNA expression in adipose tissue of women positively correlates with adiposity (Blouin et al 2005). Similarly, Wake et al (2007) showed that central fat distribution, measured by waist/hip ratio, was associated with mRNA expression for AKR1C2 in white adipose tissue.…”

Section: Introductionmentioning

confidence: 79%

Gender-specific genetic associations of polymorphisms in ACE, AKR1C2, FTO and MMP2 with weight gain over a 10-year period

et al. 2014

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Weight gain, when it leads to overweight or obesity, is nowadays one of the major health problems. ACE, FTO, AKR1C2, TIMP4 and MMP2 genes have been implicated in previous studies on weight regulation. This study investigated the contribution of polymorphisms in these five candidate genes to the risk of weight gain over a 10-year time period. Two groups were selected from participants of the Doetinchem cohort study who were followed over a 10-year period: A stable weight group (±2 kg/10 year; n = 259) and a weight gainers group who increased their body weight by roughly 10 % ([8 kg/ 10 year; n = 237). Starting BMI was between 20 and 35 kg/m 2 and baseline age between 20 and 45 years. Selected SNPs and insert/deletion in candidate genes were measured in each group. In men, the allelic distribution of FTO rs9939609 (v 2 p = 0.005), ACE rs4340 (v 2 p = 0.006) and AKR1C2 rs12249281 (v 2 p = 0.019) differed between the weight stable and weight gainers group. Interaction between FTO rs9939609 and ACE rs4340 was observed. In women, the allelic distribution of MMP2 rs1132896 differed between the weight stable and weight gainers group (v 2 p = 0.00001). The A-allele of FTO was associated with a 1.999 higher risk of gaining weight in men (OR 1.99, p = 0.020), while in women, the C-allele of MMP2 was associated with a 2.509 higher risk of weight gain (OR 2.50, p = 0.001) over the 10-year period. We found that FTO in men and MMP2 in women are associated with weight gain over a 10-year follow-up period.

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“…AKR1C activity and messenger RNA (mRNA) have also been detected in subcutaneous and OM adipose tissue in women, and OM AKR1C of progesterone is highest in women with visceral obesity. Significant positive correlations are also found between OM AKR1C activity and OM adipocyte diameter and OM adipose tissue lipoprotein lipase activity (Blouin et al, 2005 The aldosterone-regulated sodium reabsorption pathway shows enrichment with the insulin receptor (INSR), insulin receptor substrate 2 (IRS-2), and phosphatidylinositol 3-kinase (PI3K) R1 genes. Muscle-specific INSR knockout mice (fat-specific disruption of the INSR gene) exhibit a muscle-specific reduction in receptor content and early signaling events (Bruning et al, 1998).…”

Section: Discussionmentioning

confidence: 98%

Expression profiling based on coexpressed modules in obese prepubertal children

Zhang

Yao²,

Wu³

2012

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to identify related genes and the underlying molecular mechanisms in obese patients who show a series of clinical and metabolic abnormalities known as metabolic syndrome. We identified expression profiles through a coexpression network. In addition, a similarity matrix and expression modules were constructed based on domain and pathway enrichment analysis. The genes in module 1 were mainly involved in the metabolism of xenobiotics by cytochrome P450, aldosterone-regulated sodium reabsorption, and focal adhesion owing to the presence of aldo/ketoreductase, basic helix-loop-helix, von Willebrand factor, Frizzled-related domain, and other domains. The genes in module 3 may be involved in cell cycle (hsa04110) and DNA replication (hsa03030) pathways through minichromosome maintenance, serine/threonine protein kinase, the protein kinase domain, and other domains. We analyzed the published molecular mechanisms of obesity and found many genes and pathways that have not been given enough attention and require further confirmation.

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Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women

Abstract: -The, and André Tchernof. Expression and activity of steroid aldoketoreductases 1C in omental adipose tissue are positive correlates of adiposity in women.

Cited by 55 publications

References 40 publications

Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes

Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes

Gender-specific genetic associations of polymorphisms in ACE, AKR1C2, FTO and MMP2 with weight gain over a 10-year period

Expression profiling based on coexpressed modules in obese prepubertal children

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