Jacques Mailloux

Regional differences in adipose tissue metabolism in women : Minor effect of obesity and body fat distribution

Studies comparing adipose tissue metabolism in central versus peripheral fat depots have generated equivocal data. We examined whether regional differences in abdominal subcutaneous and omental adipose tissue metabolism in women exist and whether they persist across the spectrum of body fatness and abdominal adiposity values. We measured adipocyte size; lipoprotein lipase (LPL) activity; and basal, isoproterenol-, forskolin-, and dibutyryl cAMP–stimulated lipolysis in adipose tissue or mature adipocytes isolated from the omental and subcutaneous fat depots in a sample of 55 healthy women undergoing elective gynecological surgery. Measures of body fat mass and body fat distribution were also obtained by dual-energy X-ray absorptiometry and computed tomography. Subcutaneous adipocytes were significantly larger than omental adipocytes (P < 0.0001). LPL activity expressed as a function of cell number was significantly higher in subcutaneous versus omental adipose tissue (P < 0.0001). Basal, isoproterenol-stimulated, dibutyryl cAMP–stimulated (10−3 mol/l) and forskolin-stimulated (10−5 mol/l) lipolysis (expressed as a function of cell number) were all significantly higher in subcutaneous versus omental adipocytes (P < 0.05 to P < 0.0001). However, the response of omental adipocytes to lipolytic stimuli tested (fold increase over basal level) was significantly greater in magnitude compared with subcutaneous adipocytes (P < 0.01). These differences were relatively constant across total body fat mass and visceral adipose tissue area tertiles. In conclusion, compared with adipocytes from the omental fat compartment, subcutaneous adipocytes are larger, have higher LPL activity, and are more lipolytic on an absolute basis, which may reflect a higher fat storage capacity in this depot in women. In contrast, omental adipocytes display greater relative responsiveness to both adrenergic receptor–and postreceptor-acting agents compared with subcutaneous adipocytes. Overall and visceral obesity have only minor effects on regional differences in adipose tissue metabolism.

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.

Effects of androgens on adipocyte differentiation and adipose tissue explant metabolism in men and women.

Objective  To examine the effects of aromatizable or nonaromatizable androgens on abdominal subcutaneous (SC) and omental (OM) adipose tissue lipid metabolism and adipogenesis in men and women.

Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis

The objective was to examine pathways of androgen metabolism in abdominal adipose tissue in women. Abdominal subcutaneous (SC) and omental (OM) adipose tissue samples were surgically obtained in women. Total RNA was isolated from whole adipose tissue samples and from primary preadipocyte cultures before and after induction of differentiation. Expression levels of several steroid-converting enzyme transcripts were examined by real-time RT-PCR. Androgen conversion rates were also measured. We found higher expression levels in SC compared with OM adipose tissue for type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD-1; P < 0.05), for aldo-keto reductase 1C3 (AKR1C3; P < 0.0001), for AKR1C2 (P < 0.0001), and for the androgen receptor (P < 0.0001). 17beta-HSD-2 mRNA levels were lower in SC adipose tissue (P < 0.05). Induction of adipocyte differentiation led to significantly increased expression levels in SC cultures for AKR1C3 (4.7-fold, P < 0.01), 11-cis-retinol dehydrogenase (6.9-fold, P < 0.02), AKR1C2 (5.6-fold, P < 0.004), P-450 aromatase (5.7-fold, P < 0.02), steroid sulfatase (3.1-fold, P < 0.02), estrogen receptor-beta (11.8-fold, P < 0.01), and the androgen receptor (4.0-fold, P < 0.0005). Generally similar but nonsignificant trends were obtained in OM cultures. DHT inactivation rates increased with differentiation, this effect being mediated by dexamethasone alone, through a glucocorticoid receptor-dependent mechanism. In conclusion, higher mRNA levels of enzymes synthesizing and inactivating androgens are found in differentiated adipocytes, consistent with higher androgen-processing rates in these cells. Glucocorticoid-induced androgen inactivation may locally modulate the exposure of adipose cells to active androgens.

Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women

Sixty-three healthy post-menopausal women participated in the study aimed at determining the efficiency of percutaneous administration of estradiol (E2) giving physiological plasma levels of the estrogen to provide an efficient relief of climacteric and urogenital symptoms. Among these women, 31 had previous hysterectomy and were randomly allocated to one of the two estrogen replacement therapies while, similarly, the 32 women having an uterus were randomly divided between two groups who received in addition to estrogens, micronized oral progesterone. As estrogen, women received either E2 by percutaneous administration (Oestrogel) or oral conjugated estrogens (Premarin). With Oestrogel, serum E2 and estrone levels were within those seen during premenopause and showed a ratio close to 1.0. Climacteric symptoms were reduced or eliminated similarly in all groups. No changes was noticed on the concentration of serum angiotensinogen with Oestrogel therapy while a 2.5-fold increase was found in women receiving Premarin. As indicated by the 24-week endometrial biopsy, the progestational response induced by oral progesterone at the dose used was sufficient in twenty out of thirty-two women to cause endometrial atrophy, thus suggesting the need for higher amounts of micronized progesterone in a proportion of women. The present data also indicate that Oestrogel provides efficient relief of climacteric and urogenital symptoms without exerting any detectable effect on hepatic function while maintaining the ratio of serum E2/E1 at the physiological value of 1.0.

Macrophage Migration Inhibitory Factor Is Involved in a Positive Feedback Loop Increasing Aromatase Expression in Endometriosis

Immune-endocrine interplay may play a major role in the pathogenesis of endometriosis. In the present study, we have investigated the interaction between macrophage migration inhibitory factor (MIF), a major pro-inflammatory and growth-promoting factor markedly expressed in active endometriotic lesions, and estradiol (E(2)) in ectopic endometrial cells. Our data showed a significant increase of MIF protein secretion and mRNA expression in endometriotic cells in response to E(2). MIF production was blocked by Fulvestrant, an estrogen receptor (ER) antagonist, and induced by ERα and ERβ selective agonists propyl-pyrazole-triol (PPT) and diarylpropionrile (DPN), respectively, thus demonstrating a specific receptor-mediated effect. Cell transfection with MIF promoter construct showed that E(2) significantly stimulates MIF promoter activity. Interestingly, our data further revealed that MIF reciprocally stimulates aromatase protein and mRNA expression via a posttranscriptional mRNA stabilization mechanism, that E(2) itself can upregulate aromatase expression, and that inhibition of endogenous MIF, using MIF specific siRNA, significantly inhibits E(2)-induced aromatase. Thus, the present study revealed the existence of a local positive feedback loop by which estrogen acts directly on ectopic endometrial cells to upregulate the expression of MIF, which, in turn, displays the capability of inducing the expression of aromatase, the key and rate-limiting enzyme for estrogen synthesis. Such interplay may have a considerable impact on the development of endometriosis.

Deficient expression of tumor necrosis factor receptor type 2 in the endometrium of women with endometriosis.

Problem: Tumor necrosis factor‐α (TNF‐α) is secreted mainly during the menstrual phase and has been suggested to play a role in induction of apoptosis in endometrial cells and menstrual shedding. TNF‐α receptor type 2 (TNF‐RII) is believed to play a central role in TNFα‐mediated cytotoxic, mitogenic, anti‐proliferative and apoptotic effects. The aim of this study was to assess whether TNF‐RII maybe expressed differentially in the endometrium of women with different degrees of endometriosis.

Soluble Human IL-1 Receptor Type 2 Inhibits Ectopic Endometrial Tissue Implantation and Growth : Identification of a Novel Potential Target for Endometriosis Treatment

Endometriosis is often associated with a chronic pelvic immuno-inflammatory process, which is closely related to disease pathogenesis and major symptoms. Our studies led to the detection of a marked imbalance between IL-1 and its natural inhibitor IL-1 receptor type 2 (IL1R2) in women with endometriosis. This points to a deficiency in the local control of IL-1 that, in view of the cytokines elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development. Using an in vivo model in which human endometrial tissue was inoculated into nude mice and left to establish before any further treatment, our data showed that sIL1R2 interferes with the capability of endometrial tissue to invade, grow, disseminate, and stimulate angiogenesis into the host tissue. sIL1R2 significantly down-regulated the expression of major cell adhesion receptors (αv and β3 integrins), matrix metalloproteinases (MMP-2 and -9), and vascular endothelial cell growth factor. Interestingly, treatment with sILR2 (5 μg/kg) led to a concomitant upregulation of matrix metalloproteinases natural inhibitors (TIMP1 and TIMP2) and down-regulation of BclII, a potent anti-apoptotic protein. This creates an imbalance between pro- and anti-proteolytic and apoptotic factors and may further contribute to IL1R2 growth-inhibitory effects. This study provides evidence that sIL1R2 alters ectopic endometrial tissue growth, remodeling, and survival in vivo and may represent an interesting potential therapeutic tool.

Maternal and neonatal morbidity in instrumental deliveries with the kobayashi vacuum extractor and low forceps

Risks to the mother and newborn associated with the use of the Kobayashi Silastic vacuum extractor (n = 293) were compared with those associated with the use of low forceps (n = 468) in a retrospective chart review. Third or fourth degree perineal tears and vaginal and cervical lacerations were all observed less frequently among women delivered with the vacuum extractor. The need for post‐partum bladder catheterization was also reduced for these women. Babies born by the means of the vacuum extractor ran an increased risk of cephalhematoma and neonatal jaundice. No difference in major neonatal morbidity was observed between the two groups. The Kobayashi instrument appears to be a useful alternative to forceps in low vaginal instrumental deliveries.

Circulating 5α-dihydrotestosterone, abdominal obesity and adipocyte characteristics in women

Abstract Background: The association between circulating androgen levels and fat distribution in women has been widely inconsistent among existing studies. Objective: We sought to investigate the relation between plasma adrenal and gonadal androgen levels and body fat distribution, as well as abdominal adipocyte characteristics. Methods: Paired omental and subcutaneous adipose tissue samples were surgically obtained from 60 women (age, 47±5 years; body mass index, 26±5 kg/m2) undergoing gynecological surgery. Body composition and fat distribution were measured by dual-energy X-ray absorptiometry and computed tomography, respectively. Adipocyte diameter, basal lipolysis, and heparin-releasable lipoprotein lipase activity were measured. Steroids were quantified using high-performance gas chromatography and mass spectrometry. Results: Significant negative associations were found between plasma dihydrotestosterone (DHT) levels and total adiposity (body mass index, r=–0.35, p<0.05; fat mass, r=–0.31, p<0.05) as well as computed tomography assessments of abdominal adiposity (r=–0.30, p<0.05 and r=–0.44, p<0.005 for subcutaneous and visceral adipose tissue area, respectively). The association between DHT levels and visceral adipose tissue area was independent of total body fat mass. A significant negative association was also observed between plasma DHT and omental adipocyte diameter (r=–0.27, p<0.05). When expressed as the omental/subcutaneous ratio, heparin-releasable lipoprotein lipase activity was negatively and significantly related to plasma DHT, androstenedione, and dehydroepiandrosterone (DHEA) levels. Conclusion: Abdominally obese women with large, metabolically active omental adipocytes appear to be characterized by reduced endogenous levels of DHT. The assumption that high androgen levels are associated with an android body fat distribution pattern in women should be critically re-examined.