Increased adipose tissue indices of androgen catabolism and aromatization in women with metabolic dysfunction

Abstract

Background: Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue. Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity. Methods: Samples from 40 bariatric candidates (31 women, 9 men) were included in the study. Visceral (VAT) and subcutaneous adipose tissue (SAT) were collected during surgery. Adipose tissue morphology was measured by a combination of histological staining and semi-automated quantification. Following extraction, intra-adipose and plasma steroid concentrations were determined by liquid chromatography, electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Aromatase activity was estimated using product-over-substrate ratio, while AKR1C2 activity was measured directly by fluorogenic probe. Gene expression was measured by quantitative PCR. Results: VAT aromatase activity was positively associated with VAT adipocyte hypertrophy (p-valueadj < 0.01) and negatively with plasma HDL-cholesterol (p-valueadj < 0.01), while SAT aromatase activity predicted dyslipidemia in women even after adjustment for waist circumference, age and hormonal contraceptive use. We additionally compared women with high and low visceral adiposity index (VAI) and found that VAT excess is characterized by adipose tissue dysfunction, increased androgen catabolism mirrored by increased AKR1C2 activity and higher aromatase expression and activity indices. Conclusion: In women, increased androgen catabolism or aromatization is associated with visceral adiposity and adipose tissue dysfunction.

Increased Adipose Tissue Indices of Androgen Catabolism and Aromatization in Women With Metabolic Dysfunction

“…Unfortunately, due to some missing anthropometric data, analysis of adipose tissue dysfunction in men was not possible. Because of sample size, which would have given analyses of limited meaning, data collected on male participants are presented in supplemental Table S3 ( 43 ). Anthropometric and metabolic characteristics of female participants are listed in Table 1 , while steroid hormone concentrations can be found in Table 2 .…”

“…Following derivatization, samples were suspended in water:acetonitrile (1:1) and loaded to liquid chromatography vials. Lower limits of quantification can be found in supplemental Table 1 (Table S1 ( 43 )). Accuracy, measured as percentage relative mean error, and precision, as percentage relative standard deviation, for estrogens and glucocorticoids have already been published ( 42 ), while for androgens, precision ranged between 14.8% and 6.1% and accuracy between 8.6% and 4.3%.…”

“…Chromatographic separation was achieved on a Kinetex C18 column (3 × 150 mm, 2.6 μm; Phenomenex, UK) fitted with a KrudKatcher Ultra In-Line Filter (Phenomenex, UK) with water and methanol as mobile phase, with ammonium fluoride (50 μM) as modifier. Lower limits of quantification are found in supplemental Table S1 ( 43 ). Precision ranged between 11.4% (5α-dihydrotestosterone []) and 6.3% (estradiol) while accuracy between 5.8 (5α-DHT) and 7.0 (estrone).…”

“…Table S2 ( 43 ) lists the target, sequence, and length of the primers used. Primers were designed using NCBI primer design tool ( https://www.ncbi.nlm.nih.gov/tools/primer-blast/ ) and synthetized by IDT (Integrated DNA Technology, Coralville, IA, USA).…”

Effects of a New Group of Antidiabetic Drugs in Metabolic Diseases

“…Weight reduction may contribute to bone loss due to the direct effect of reduced soft tissue mass on bone [88]. In addition, the decrease in adipose tissue may reduce aromatase activity, decreasing estradiol levels and increasing bone turnover [90][91][92]. Finally, decreased sodium transport in the proximal convoluted tubule facilitates an increase in serum phosphorus levels, which would stimulate para thyroid hormone (PTH), enhancing bone turnover and increasing the risk of fractures [93].…”