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.

Expression profiles and gene set enrichment analysis of the transcriptomes from the cancer tissue, white adipose tissue and paracancer tissue with colorectal cancer

“…These pathways are related to metabolism, genetic information processing, and environmental information processing. The alteration of steroid biosynthesis regulates lipid metabolism, and the change in local steroid concentration can cause abnormal adipose tissue function, such as dyslipogenesis or abnormal production of adipokines, eventually leading to lipid metabolism disorder ( Ostinelli et al, 2022 ; Wawrzkiewicz-Jałowiecka, Lalik & Soveral, 2021 ). Twenty candidate genes of interest were enriched in steroid biosynthesis, and the leading edge included 14 genes ( Fig.…”

Adipocyte regulation of cancer stem cells

“…Estrogens are synthesized from androgens using cytochrome P450 aromatase, which is encoded by the CYP19 gene 66 . After menopause, estrogen biosynthesis is primarily mediated by peripheral aromatization of androgen precursors in adipose tissue 67 …”

“…66 After menopause, estrogen biosynthesis is primarily mediated by peripheral aromatization of androgen precursors in adipose tissue. 67 Although exposure to estradiol promotes the growth and maintenance of papillary thyroid CSCs 68 and the importance of estrogen in breast cancer is well established, the effects of estrogen on breast CSCs are not fully understood. Several studies have reported that estrogens alone do not increase, and breast CSCs lack expression of estrogen receptor (ER) or express it at very low levels.…”

“… 66 After menopause, estrogen biosynthesis is primarily mediated by peripheral aromatization of androgen precursors in adipose tissue. 67 …”

Androgen excess: a hallmark of polycystic ovary syndrome

“…These findings are in line with those of a previous study reporting that insulin significantly stimulates A4 and T production in SAT ( 58 ). Conversely, in the VAT of women with obesity, increased aromatase activity, representing the hypertrophy of adipocyte, parallels the increased androgen catabolism via enhancing AKR1C2 function ( 59 ). In addition, the expression level of AR in the VAT may be higher than that in the SAT of women with PCOS, making the VAT more vulnerable to androgen exposure ( 35 ).…”