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

2012 ◽  
Vol 302 (8) ◽  
pp. E941-E949 ◽  
Author(s):  
Alain Veilleux ◽  
Julie-Anne Côté ◽  
Karine Blouin ◽  
Mélanie Nadeau ◽  
Mélissa Pelletier ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Accumulation ◽  
Tissue Sample ◽  
Subcutaneous Fat ◽  
Human Adipose Tissue ◽  
Preadipocyte Differentiation ◽  
Omental Adipose Tissue ◽  
Human Preadipocytes ◽  
Omental Fat ◽  
G3pdh Activity

Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3α-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 3α/β-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 < 0.05). Maximal dexamethasone (1 μM) stimulation of DHT inactivation was higher in omental compared with subcutaneous fat from men as well as subcutaneous and omental fat from women ( P < 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 = 0.24, n = 26, P < 0.01). siRNA-induced downregulation of AKR1C2, but not AKR1C1 or AKR1C3, significantly reduced basal and glucocorticoid-induced androgen inactivation rates ( P < 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.

scholarly journals Androgen generation in adipose tissue in women with simple obesity – a site-specific role for 17β-hydroxysteroid dehydrogenase type 5

2004 ◽  
Vol 183 (2) ◽  
pp. 331-342 ◽  
Author(s):  
Marcus Quinkler ◽  
Binayak Sinha ◽  
Jeremy W Tomlinson ◽  
Iwona J Bujalska ◽  
Paul M Stewart ◽  
...  
Keyword(s):  
Weight Loss ◽  
Adipose Tissue ◽  
Subcutaneous Fat ◽  
Human Adipose Tissue ◽  
Hydroxysteroid Dehydrogenase ◽  
Rt Pcr ◽  
Androgen Synthesis ◽  
The Metabolic Syndrome ◽  
Simple Obesity ◽  
Omental Fat

Women with polycystic ovary syndrome (PCOS) have high circulating androgens, thought to originate from ovaries and adrenals, and frequently suffer from the metabolic syndrome including obesity. However, serum androgens are positively associated with body mass index (BMI) not only in PCOS, but also in simple obesity, suggesting androgen synthesis within adipose tissue. Thus we investigated androgen generation in human adipose tissue, including expression of 17β-hydroxysteroid dehydrogenase (17β-HSD) isozymes, important regulators of sex steroid metabolism. Paired omental and subcutaneous fat biopsies were obtained from 27 healthy women undergoing elective abdominal surgery (age range 30–50 years; BMI 19.7–39.2 kg/m2). Enzymatic activity assays in preadipocyte proliferation cultures revealed effcient conversion of androstenedione to testosterone in both subcutaneous and omental fat. RT-PCR of whole fat and preadipocytes of subcutaneous and omental origin showed expression of 17β-HSD types 4 and 5, but no relevant expression of 17β-HSD types 1, 2, or 3. Microarray analysis confirmed this expression pattern (17β-HSD5>17β-HSD4) and suggested a higher expression of 17β-HSD5 in subcutaneous fat. Accordingly, quantitative real-time RT-PCR showed significantly higher expression of 17β-HSD5 in subcutaneous compared with omental fat (P<0.05). 17β-HSD5 expression in subcutaneous, but not omental, whole fat correlated significantly with BMI (r=0.51, P<0.05). In keeping with these findings, 17β-HSD5 expression in subcutaneous fat biopsies from six women taking part in a weight loss study decreased significantly with weight loss (P<0.05). A role for 17β-HSD5 in adipocyte differentiation was further supported by the observed increase in 17β-HSD5 expression upon differentiation of stromal preadipocytes to mature adipocytes (n=5; P<0.005), which again was higher in cells of subcutaneous origin. Functional activity of 17β-HSD5 also significantly increased with differentiation, revealing a net gain in androgen activation (androstenedione to testosterone) in subcutaneous cultures, contrasting with a net gain in androgen inactivation (testosterone to androstenedione) in omental cultures. Thus, human adipose tissue is capable of active androgen synthesis catalysed by 17β-HSD5, and increased expression in obesity may contribute to circulating androgen excess.

scholarly journals Expression of Genes Related to Prostaglandin Synthesis or Signaling in Human Subcutaneous and Omental Adipose Tissue: Depot Differences and Modulation by Adipogenesis

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Andréanne Michaud ◽  
Nicolas Lacroix-Pépin ◽  
Mélissa Pelletier ◽  
Marleen Daris ◽  
Laurent Biertho ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mrna Expression ◽  
Rt Pcr ◽  
Preadipocyte Differentiation ◽  
Omental Adipose Tissue ◽  
Expression Of Genes ◽  
Induced Changes ◽  
Omental Fat ◽  
Adipose Tissue Depot ◽  
Cox 1

Objectives. (1) To examine depot-specific PGE2and PGF2αrelease and mRNA expression of enzymes or receptors involved in PG synthesis or signaling in human adipose tissues; (2) to identify changes in expression of these transcripts through preadipocyte differentiation; and (3) to examine associations between adipose tissue mRNA expression of these transcripts and adiposity measurements.Methods. Fat samples were obtained surgically in women. PGE2and PGF2αrelease by preadipocytes and adipose tissue explants was measured. Expression levels of mRNA coding for enzymes or receptors involved in PG synthesis or signaling were measured by RT-PCR.Results. Cultured preadipocytes and explants from omental fat released more PGE2and PGF2αthan those from the subcutaneous depot and the corresponding transcripts showed consistent depot differences. Following preadipocyte differentiation, expression of PLA2G16 and PTGER3 mRNA was significantly increased whereas COX-1, COX-2, PTGIS, and PTGES mRNA abundance were decreased in both compartments (P≤0.01for all). Transcripts that were stimulated during adipogenesis were those that correlated best with adiposity measurements.Conclusion. Cells from the omental fat compartment release more PGE2and PGF2αthan those from the subcutaneous depot. Obesity modulates expression of PG-synthesizing enzymes and PG receptors which likely occurs through adipogenesis-induced changes in expression of these transcripts.

scholarly journals Release of Inflammatory Mediators by Human Adipose Tissue Is Enhanced in Obesity and Primarily by the Nonfat Cells: A Review

2010 ◽  
Vol 2010 ◽  
pp. 1-20 ◽  
Author(s):  
John N. Fain
Keyword(s):  
Adipose Tissue ◽  
In Vitro Release ◽  
Human Adipose Tissue ◽  
Fat Cells ◽  
Omental Adipose Tissue ◽  
Subcutaneous Adipose ◽  
Circulating Levels ◽  
Pai 1

This paper considers the role of putative adipokines that might be involved in the enhanced inflammatory response of human adipose tissue seen in obesity. Inflammatory adipokines [IL-6, IL-10, ACE, TGFβ1, TNFα, IL-1β, PAI-1, and IL-8] plus one anti-inflammatory [IL-10] adipokine were identified whose circulating levels as well as in vitro release by fat are enhanced in obesity and are primarily released by the nonfat cells of human adipose tissue. In contrast, the circulating levels of leptin and FABP-4 are also enhanced in obesity and they are primarily released by fat cells of human adipose tissue. The relative expression of adipokines and other proteins in human omental as compared to subcutaneous adipose tissue as well as their expression in the nonfat as compared to the fat cells of human omental adipose tissue is also reviewed. The conclusion is that the release of many inflammatory adipokines by adipose tissue is enhanced in obese humans.

scholarly journals Hypoxia Alters the Expression of Dipeptidyl Peptidase 4 and Induces Developmental Remodeling of Human Preadipocytes

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Helena H. Chowdhury ◽  
Jelena Velebit ◽  
Nataša Radić ◽  
Vito Frančič ◽  
Marko Kreft ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transmembrane Protein ◽  
Human Adipose Tissue ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase 4 ◽  
Hypoxic Conditions ◽  
Human Preadipocytes ◽  
Developmental Remodeling

Dipeptidyl peptidase 4 (DPP4), a transmembrane protein, has been identified in human adipose tissue and is considered to be associated with obesity-related type 2 diabetes. Since adipose tissue is relatively hypoxic in obese participants, we investigated the expression of DPP4 in human preadipocytes (hPA) and adipocytes in hypoxia, during differentiation and upon insulin stimulation. The results show that DPP4 is abundantly expressed in hPA but very sparsely in adipocytes. During differentiationin vitro, the expression of DPP4 in hPA is reduced on the addition of differentiation medium, indicating that this protein can be hPA marker. Long term hypoxia altered the expression of DPP4 in hPA. Inin vitrohypoxic conditions the protease activity of shed DPP4 is reduced; however, in the presence of insulin, the increase in DPP4 expression is potentiated by hypoxia.

scholarly journals The in vitro secretion of human leptin is gender-dependent but independent of the body mass index of the donors

2000 ◽  
pp. 711-714 ◽  
Author(s):  
C Menendez ◽  
R Baldelli ◽  
M Lage ◽  
X Casabiell ◽  
V Pinero ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Adipose Tissue ◽  
Body Mass ◽  
Tissue Sample ◽  
Secretory Activity ◽  
The Body ◽  
Secretory Rate ◽  
Omental Adipose Tissue

OBJECTIVE: Leptin is an adipocyte-secreted hormone acting as a signal to the central nervous system, where it regulates energy homeostasis and neuroendocrine processes. Leptin plasma levels are mainly regulated by the percentage of body fat, but are also controlled by several metabolic and nutritional variables. Data regarding leptin secretion suggest that it is gender regulated, and higher levels are present in women than men; however, the biological basis for this sex-related difference is unknown. To clarify those points, a systematic study with tissue cultures from human omental adipose tissue was performed. DESIGN AND METHODS: Surgically obtained samples from 137 patients (68 women, 69 men) were evaluated. The assay was standardized in periods of 24 h ending at 96 h. Each adipose tissue sample from a single donor was incubated in triplicate and leptin results expressed as the mean of the integrated secretion into the medium (nanograms of leptin/g tissue per time). RESULTS: Tissue adipose cultures showed a steady leptin secretion throughout the 96 h studied, with the peak of secretory activity reached at 48 h; afterwards, the in vitro secretion reached a plateau state. Spontaneous leptin secretion in the 24 h and 48 h period, as well as the area under the curve analyzed in the 0-48 h period, showed a gender-based difference that was significantly (P<0. 05) higher in women than in men. When data of spontaneous leptin secretion were correlated with the body mass index (BMI) of the donors, no correlation was found. This suggests that in vivo leptin levels are dependent on the total amount of fat of the individual, but independent of the leptin secretory rate by the adipose tissue of the donor. CONCLUSIONS: Leptin secretion from omental adipose tissue in vitro is: (i) significantly higher in samples from women than in samples from men; and (ii) not correlated with the BMI, showing that in vitro leptin secretion is not related to the adiposity of the donor.

scholarly journals TSH stimulates leptin secretion by a direct effect on adipocytes

2003 ◽  
Vol 176 (1) ◽  
pp. 7-12 ◽  
Author(s):  
C Menendez ◽  
R Baldelli ◽  
JP Camina ◽  
B Escudero ◽  
R Peino ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Direct Action ◽  
Human Adipose Tissue ◽  
Pituitary Hormones ◽  
Organ Cultures ◽  
Omental Adipose Tissue ◽  
Thyroid Axis ◽  
The Central Nervous System

Leptin is a circulating hormone secreted by adipose tIssue which acts as a signal to the central nervous system where it regulates energy homeostasis and neuroendocrine processes. Although leptin modulates the secretion of several pituitary hormones, no information is available regarding a direct action of pituitary products on leptin release. However, it has been pointed out that leptin and TSH have a coordinated pulsatility in plasma. In order to test a direct action of TSH on in vitro leptin secretion, a systematic study of organ cultures of human omental adipose tIssue was performed in samples obtained at surgery from 34 patients of both sexes during elective abdominal surgery. TSH powerfully stimulated leptin secretion by human adipose tIssue in vitro. In contrast, prolactin, ACTH, FSH and LH were devoid of action. These results suggest that leptin and the thyroid axis maintain a complex and dual relationship and open the possibility that plasmatic changes in TSH may contribute to the regulation of leptin pulses.

Lipogenesis and lipoprotein lipase in human adipose tissue: reproducibility of measurements and relationships with fat cell size

1984 ◽  
Vol 62 (12) ◽  
pp. 1448-1452 ◽  
Author(s):  
Roland Savard ◽  
Yves Deshaies ◽  
Jean-Pierre Després ◽  
Martine Marcotte ◽  
Ludwik Bukowiecki ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipoprotein Lipase ◽  
Lipase Activity ◽  
Tissue Sample ◽  
High Reliability ◽  
Human Adipose Tissue ◽  
Cell Diameter ◽  
Lipoprotein Lipase Activity ◽  
Fat Cell ◽  
Cell Weight

Lipogenesis from glucose and lipoprotein lipase activity were investigated in humans. The reliability of measurements was quantified and correlations with fat cell weight were assessed. Twenty-four subjects (7 women, 17 men) were studied twice within a 2-week period, along with 17 additional male subjects who were studied once and used only in the correlation analyses. All subjects were not regularly involved in an exercise-training program and were between 18 and 30 years of age. Following an overnight fast, adipose tissue specimens were obtained by suprailiac biopsy and fat cells were collagenase isolated. Mean fat cell weight was obtained from 400 to 500 cell diameter determinations per subject. Basal and insulin-stimulated fat cell lipogenesis from glucose were determined using D-[U-14C]glucose and were reported in nanomoles of glucose per hour per 106 cells. Adipose tissue heparin-releasable lipoprotein lipase activity was also determined and expressed in micromoles of free fatty acids per hour per gram of tissue and per 106 cells. Fat cell weight, basal and insulin-stimulated lipogenesis and lipoprotein lipase activity per gram showed high reliability of measurement, interclass and intraclass coefficients being 0.83 and over. Lipoprotein lipase activity per 106 cells showed a somewhat lower degree of reliability, interclass and intraclass coefficients being, respectively, 0.69 and 0.81. On the other hand, fat cell weight was positively correlated with lipoprotein lipase activity (r = 0.80), while no significant correlation was observed between basal lipogenesis and fat cell weight. Moreover, basal lipogenesis presented no significant correlation with lipoprotein lipase activity. These results suggest that, under standardized conditions, and from a single tissue sample, human adipose tissue lipoprotein lipase activity and fat cell lipogenesis can be measured with a satisfactory level of reliability. They also suggest that lipoprotein lipase activity is highly related with adipocyte lipid content.

scholarly journals Retinoic acid and vitamin D(3) powerfully inhibit in vitro leptin secretion by human adipose tissue

2001 ◽  
Vol 170 (2) ◽  
pp. 425-431 ◽  
Author(s):  
C Menendez ◽  
M Lage ◽  
R Peino ◽  
R Baldelli ◽  
P Concheiro ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Retinoic Acid ◽  
Energy Homeostasis ◽  
Human Adipose Tissue ◽  
Tissue Samples ◽  
Omental Adipose Tissue ◽  
Vitamin D 3 ◽  
Gender Based

Leptin, the product of the ob gene, is secreted into the circulation by white adipose tissue; its major role being to participate in the regulation of energy homeostasis. Plasma leptin levels are mainly determined by the relative adiposity of the subject; however, the great dispersion of values for any given body mass index and the noteworthy gender-based differences indicate that other factors are operating. Steroid hormones actively participate in the regulation of leptin secretion; however, non-steroid nuclear hormones have either not been studied or have provided contradictory results. In order to understand the role of hormones of the non-steroid superfamily such as 3,5,3'-tri-iodothyronine (T(3)), vitamin D(3) and retinoic acid (RA) in the control of leptin secretion, in the present work doses of 10(-9), 10(-8) and 10(-7) M of these compounds have been studied on in vitro leptin secretion. The organ culture was performed with omental adipose tissue samples from healthy donors (n=28). T(3) was devoid of effect at any dose studied, while an inhibition of leptin secretion was observed with 9-cis-RA (slight) and all-trans-RA (potent). Interestingly, vitamin D(3) exerted a powerfully inhibitory role at the doses studied, and its action was synergistic with all-trans-RA. In conclusion, in vitro leptin secretion by human adipose tissue is negatively controlled by either RA or vitamin D(3). The clinical significance of leptin regulation by this superfamily of nuclear receptors remains to be ascertained.

scholarly journals Hyperglycemia-induced changes in resistin gene expression in white adipose tissue in piglets

2015 ◽  
Vol 15 (3) ◽  
pp. 667-679 ◽  
Author(s):  
Ewa Ocłoń ◽  
Joanna Zubel-Łojek ◽  
Anna Latacz ◽  
Krystyna Pierzchała-Koziec
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Opposite Effect ◽  
Mrna Level ◽  
Physiological Saline ◽  
Glycemic Status ◽  
Omental Adipose Tissue ◽  
Induced Changes ◽  
Omental Fat ◽  
Resistin Mrna

Abstract Previous data strongly indicated that resistin, an adipocyte-derived signalling peptide, plays an important role in metabolism and glucose homeostasis. Thus, the aim of the present study was to examine changes in synthesis and concentration of resistin in white adipose tissue in response to hyperglycemia in piglets. In order to develop hyperglycemia, piglets (10-week-old, Polish Landrace fatteners, female) received intraperitoneal (ip) injection of 150 mg streptozotocin (HI, n=6) or 60 mg synthetic glucocorticoid (HII, n=6). An injection of NaCl physiological saline was used as a control (n=6). Plasma resistin level was significantly higher in HII group compared with the control, while no difference was observed in HI. In epicardial adipose tissue (EAT ) the resistin mRNA level significantly increased whereas the opposite effect was observed for omental fat tissue (OAT ) in both experimental groups. Additionally, the resistin concentration did not change in EAT ; however, it was decreased in omental adipose tissue in response to hyperglycemia. The results obtained indicate that activity of resistin strongly depends on glycemic status as well as adipose tissue localization.

scholarly journals Expression profiling of 11β-hydroxysteroid dehydrogenase type-1 and glucocorticoid-target genes in subcutaneous and omental human preadipocytes

2006 ◽  
Vol 37 (2) ◽  
pp. 327-340 ◽  
Author(s):  
I J Bujalska ◽  
M Quinkler ◽  
J W Tomlinson ◽  
C T Montague ◽  
D M Smith ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Target Genes ◽  
Adipocyte Differentiation ◽  
Human Adipose Tissue ◽  
Fat Accumulation ◽  
Visceral Fat Accumulation ◽  
Human Preadipocytes ◽  
Upregulated Genes ◽  
Microarray Technique

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes and cancer. Although obesity is a multi-factorial heterogeneous condition, fat accumulation in visceral depots is most highly associated with these risks. Pathological glucocorticoid excess (i.e. in Cushing’s syndrome) is a recognised, reversible cause of visceral fat accumulation. The aim of this study was to identify depot-specific glucocorticoid-target genes in adipocyte precursor cells (preadipocytes) using Affymetrix microarray technique. Confluent preadipocytes from subcutaneous (SC) and omental (OM) adipose tissue collected from five female patients were treated for 24 h with 100 nM cortisol (F), RNA was pooled and hybridised to the Affymetrix U133 microarray set. We identified 72 upregulated and 30 downregulated genes by F in SC cells. In OM preadipocytes, 56 genes were increased and 19 were decreased. Among the most interesting were transcription factors, markers of adipocyte differentiation and glucose metabolism, cell adhesion and growth arrest protein factors involved in G-coupled and Wnt signalling. The Affymetrix data have been confirmed by quantitative real-time PCR for ten specific genes, including HSD11B1, GR, C/EBPα, C/EBPβ, IL-6, FABP4, APOD, IRS2, AGTR1 and GHR. One of the most upregulated genes in OM but not in SC cells was HSD11B1. The GR was similarly expressed and not regulated by glucocorticoids in SC and OM human preadipocytes. C/EBPα was expressed in SC preadipocytes and upregulated by F, but was below the detection level in OM cells. C/EBPβ was highly expressed both in SC and in OM preadipocytes, but was not regulated by F. Our results provide insight into the genes involved in the regulation of adipocyte differentiation by cortisol, highlighting the depot specifically in human adipose tissue.

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