Effects of the Menopause Transition on Body Fatness and Body Fat Distribution

Objective : The menopause transition increases cardiovascular and metabolic disease risk, partly because of the adverse effects of estrogen deficiency on the plasma lipid-lipoprotein profile and cardiovascular function. This increased cardiovascular and metabolic disease risk may also be partially mediated by increased body fat, increased intraabdominal adipose tissue accumulation, or both. The objective of this mini-review is to summarize studies that have investigated the relationships among the menopause transition, body fatness, and body fat distribution. Research Methods and Procedures : A review of cross-sectional and longitudinal studies on menopause that examined body fatness and body fat distribution. Results : Cross-sectional reports show that the menopause transition is related to modest increases in body mass index or total fatness, although not all studies found significant effects. Increased central adiposity appears to be related to menopause, independent of advancing age, but these results are methodology dependent. An independent effect of menopause on central body fatness was noted by the use of techniques such as DEXA or computed tomography, whereas studies using circumference measures showed discrepant results. Longitudinal studies showed that the menopause transition accelerated the increase in central adiposity, although no studies quantified changes in intra-abdominal fat by imaging techniques. Discussion : Thus, additional longitudinal studies using more accurate measures of adiposity are needed to critically examine the effects of the menopause transition on total and central body fatness. Collectively, previous studies suggest that menopause is related to modest increase in total fatness and accelerated accumulation of central body fat that exceeds changes normally attributed to the aging process. These changes may increase the risk for cardiovascular and metabolic disease in aging women.     

Omental adipocyte hypertrophy relates to coenzyme Q10 redox state and lipid peroxidation in obese women

Occurrence of oxidative stress in white adipose tissues contributes to its dysfunction and the development of obesity-related metabolic complications. Coenzyme Q10 (CoQ10) is the single lipophilic antioxidant synthesized in humans and is essential for electron transport during mitochondrial respiration. To understand the role of CoQ10 in adipose tissue physiology and dysfunction, the abundance of the oxidized and reduced (CoQ10_red) isoforms of the CoQ10 were quantified in subcutaneous and omental adipose tissues of women covering the full range of BMI (from 21.5 to 53.2 kg/m²). Lean women displayed regional variations of CoQ10 redox state between the omental and subcutaneous depot, despite similar total content. Obese women had reduced CoQ10_red concentrations in the omental depot, leading to increased CoQ10 redox state and higher levels of lipid hydroperoxide. Women with low omental CoQ10 content had greater visceral and subcutaneous adiposity, increased omental adipocyte diameter, and higher circulating interleukin-6 and C-reactive protein levels and were more insulin resistant. The associations between abdominal obesity-related cardiometabolic risk factors and CoQ10 content in the omental depot were abolished after adjustment for omental adipocyte diameter. This study shows that hypertrophic remodeling of visceral fat closely relates to depletion of CoQ10, lipid peroxidation, and inflammation.     

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

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.     

Molecular Screening of the 11β‐HSD1 Gene in Men Characterized by the Metabolic Syndrome

Adipose tissue type 1 11β‐hydroxysteroid dehydrogenase (11β‐HSD1), which generates hormonally active cortisol from inactive cortisone, has been shown to play a central role in adipocyte differentiation and abdominal obesity‐related metabolic complications. The objective was to investigate whether genetic variations in the human 11β‐HSD1 gene are associated with the metabolic syndrome among French‐Canadian men. We sequenced all exons, the exon‐intron splicing boundaries, and 5′ and 3′ regions of the human 11β‐HSD1 gene in 36 men with the metabolic syndrome, as defined by the National Cholesterol Education Program‐Adult Treatment Panel III, and two controls. Three intronic sequence variants were identified: two single‐nucleotide polymorphisms in intron 3 (g.4478T>G) and intron 4 (g.10733G>C) and one insertion in intron 3 (g.4437‐4438insA). The relative allele frequency was 19.6%, 22.1%, and 19.6% for the g.4478G, g.10733C, and g.4438insA alleles, respectively. One single‐nucleotide polymorphism was identified in exon 6 (c.744G>C or G248G). The frequency of the c.744C allele was only 0.46% in a sample of 217 men. Variants were not associated with components of the metabolic syndrome except for plasma apolipoprotein B levels. In conclusion, molecular screening of the 11β‐HSD1 gene did not reveal any sequence variations that can significantly contribute to the etiology of the metabolic syndrome among French‐Canadians.     

Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity.

The present article summarizes some of the studies available on steroid hormone conversion through the specific expression of steroidogenic enzymes in adipose tissue (adipose tissue intracrinology) and discusses the potential impact of local adipose tissue steroid metabolism on the regulation of adipocyte function and other metabolic parameters. Several studies have demonstrated significant steroid hormone uptake and conversion by adipose tissues from various body sites and in various cell fractions. Activities and/or mRNAs of aromatase, 3beta-hydroxysteroid dehydrogenase (HSD), 3alpha-HSD, 11beta-HSD, 17beta-HSD, 7alpha-hydroxylase, 17alpha-hydroxylase, 5alpha-reductase and UDP-glucuronosyltransferase 2B15 have been detected in adipose tissue or adipose cells. These studies have demonstrated potentially important roles for these enzymes in obesity, central fat accumulation, and the metabolic syndrome. Future studies on adipose tissue intracrinology will contribute further to our understanding of steroid action in adipocytes.     

Circulating progesterone and obesity in men.

Progesterone can be detected in male plasma and has been considered to originate mainly from the adrenals. We have examined the association between circulating progesterone and obesity in a sample of thirty-eight lean to morbidly obese men aged 44.5 +/- 9.9 years (BMI: 44.3 +/- 12.8 kg/m (2)). Plasma concentrations of progesterone, 17-OH-progesterone as well as androstenedione, testosterone, DHT and DHEA-S were determined. Negative correlations were observed between plasma progesterone levels and body weight (r = - 0.47, p < 0.05), BMI (r = - 0.56, p < 0.001), waist circumference (r = - 0.58, p < 0.001), as well as subcutaneous adipocyte diameter (r = - 0.50, p < 0.05). Plasma levels of 17-OH-progesterone, DHEA-S, androstenedione, testosterone and DHT were also negatively associated with body weight, BMI and waist circumference. However, the ratio of 17-OH-progesterone-to-progesterone and androstenedione-to-17-OH-progesterone were not related to these variables. A positive correlation was found between circulating progesterone and DHEA-S levels (r = 0.50, p < 0.002 after adjustment for age). Accordingly, using multivariate regression analyses, the best steroid predictor of progesterone level was plasma DHEA-S. Waist circumference was the best predictor of progesterone levels in a multivariate model including steroid concentrations as well as waist circumference, BMI and subcutaneous adipocyte diameter. In conclusion, plasma progesterone was negatively associated with markers of obesity such as BMI, waist circumference and subcutaneous adipocyte diameter in this sample of men. Circulating DHEA-S level was the best steroid correlate of plasma progesterone. We suggest that the low progesterone levels observed in obese men may reflect decreased adrenal C(19) steroid production in the adrenal cortex. Further research is needed to confirm this hypothesis.     

Fat Depot‐specific Impact of Visceral Obesity on Adipocyte Adiponectin Release in Women

Our objective was to examine omental and subcutaneous adipocyte adiponectin release in women. We tested the hypothesis that adiponectin release would be reduced to a greater extent in omental than in subcutaneous adipocytes of women with visceral obesity. Omental and subcutaneous adipose tissue samples were obtained from 52 women undergoing abdominal hysterectomies (age: 47.1 ± 4.8 years; BMI: 26.7 ± 4.7 kg/m²). Adipocytes were isolated and their adiponectin release in the medium was measured over 2 h. Measures of body fat accumulation and distribution were obtained using dual‐energy X‐ray absorptiometry and computed tomography, respectively. Adiponectin release by omental and subcutaneous adipocytes was similar in lean individuals; however, in subsamples of obese or visceral obese women, adiponectin release by omental adipocytes was significantly reduced while that of subcutaneous adipocytes was not affected. Omental adipocyte adiponectin release was significantly and negatively correlated with total body fat mass (r = ?0.47, P < 0.01), visceral adipose tissue area (r = ?0.50, P < 0.01), omental adipocyte diameter (r = ?0.43, P < 0.01), triglyceride levels (r = ?0.32, P ≤ 0.05), cholesterol/high‐density lipoprotein (HDL)‐cholesterol (r = ?0.31, P ≤ 0.05), fasting glucose (r = ?0.39, P ≤ 0.01), fasting insulin (r = ?0.36, P ≤ 0.05), homeostasis model assessment index (r = ?0.39, P ≤ 0.01), and positively associated with HDL‐cholesterol concentrations (r = 0.33, P ≤ 0.05). Adiponectin release from subcutaneous cells was not associated with any measure of adiposity, lipid profile, or glucose homeostasis. In conclusion, compared to subcutaneous adipocyte adiponectin release, omental adipocyte adiponectin release is reduced to a greater extent in visceral obese women and better predicts obesity‐associated metabolic abnormalities.