Impact du taux de stéroïdes circulants sur la distribution du tissu adipeux et les altérations métaboliques chez la femme

La physiopathologie de l’obésité est un phénomène complexe qui peut amener plusieurs complications métaboliques chroniques tels que le diabète de type II et la dyslipidémie. Les dépôts de tissus adipeux n’étant pas morphologiquement homogènes, une accumulation préférentielle au niveau viscéral est associée davantage aux maladies chroniques que l’accumulation sous-cutanée. Parallèlement à ce phénomène, le dimorphisme sexuel chez l’humain témoigne de l’importance des hormones sexuelles dans la distribution des graisses. Ce phénomène semble d’autant plus important chez la femme, chez qui la ménopause entraîne une redistribution des graisses au niveau abdominal. L’objectif de ce mémoire est donc de définir la relation entre les niveaux circulants d’hormones stéroïdiennes et la distribution des graisses chez la femme, ainsi que leurs liens avec les facteurs de risque cardiométabolique. Nous avons d’abord étudié la relation entre les estrogènes circulants et l’adiposité ainsi que les paramètres métaboliques dans une cohorte de femmes ménopausées. Nous avons observé que les estrogènes étaient positivement associés à plusieurs altérations métaboliques tels que la résistance à l’insuline, mais que ce phénomène s’expliquait par la variation concomitante de masse grasse totale. Par la suite, nous avons examiné la relation des androgènes ainsi que leurs métabolites et précurseurs avec la distribution des graisses et la fonction du tissu adipeux chez la femme préménopausée. Nous avons observé que plusieurs androstanes étaient associés négativement à l’adiposité totale. De plus, certains stéroïdes, particulièrement la prégnénolone, étaient associés négativement avec la dysfonction du tissu adipeux. En somme, nos résultats pointent vers l’importance du tissu adipeux dans la régulation de la concentration d’hormones sexuelles plasmatiques.The physiopathology of obesity is a complex phenomenon resulting in many metabolic complications like type 2 diabetes and dyslipidemia. Adipose tissue depots from various locations are morphologically heterogeneous and a preferential accumulation in the visceral area is more closely associated with metabolic disorders than subcutaneous fat accumulation. The sex dimorphism observed in human body fat distribution supports important role for sex hormones in this phenomenon. The goal of this master thesis was to elucidate the relation between plasma steroid hormone levels, adipose tissue distribution and cardiometabolic risk variables in women. First, we studied the relation between circulating estrogens and adiposity as well as metabolic parameters in menopausal women. We observed positive associations between estrogens and metabolic alterations such as insulin resistance, but these associations were explained by the concomitant variation of total body fat mass. Second, we investigated the associations between androgens, their metabolites and precursors, with adipose tissue distribution and function in premenopausal women. We observed that many androstanes were negatively related with total adiposity. Moreover, some steroids, especially pregnenolone were negatively associated with markers of adipose tissue dysfunction. Together, ours results point toward the importance of adipose tissue in the regulation of circulating sex hormones

Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women

The relationship between circulating estrogen levels and cardiometabolic risk factors such as insulin resistance is unclear in postmenopausal women. High estradiol (E2) levels have been reported to predict increased risk of type 2 diabetes in this population. We aimed to examine associations among estrogen levels, adiposity measurements, and cardiometabolic risk variables including insulin resistance in postmenopausal women. One hundred-one healthy participants (mean ± SD: age 57 ± 4 yr, BMI 27.9 ± 4.8 kg/m2) were included in the analysis. Fifteen plasma steroids or metabolites were measured by liquid chromatography-tandem mass spectrometry. Insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp. Body composition and fat distribution were determined with hydrostatic weighing and computed tomography, respectively. Blood lipids and circulating cytokines were also measured. Circulating E2 was positively correlated with all adiposity indexes (r = 0.62 to 0.42, P < 0.0001) except waist-to-hip ratio. E2 was positively correlated with VLDL-cholesterol, plasma-, VLDL-, and HDL-triglyceride levels (r = 0.31 to 0.24, P < 0.02) as well as with hs-CRP and IL-6 (r = 0.52 and 0.29, P < 0.005) and negatively with HDL-cholesterol, adiponectin, and insulin sensitivity (r = −0.36 to −0.20, P < 0.02). With adjustments for percent body fat, correlations between E2 and metabolic risk variables were no longer significant. Similar results were observed for circulating estrone (E1) and estrone-sulfate (E1-S) levels. In conclusion, circulating estrogen concentrations are proportional to adipose mass in postmenopausal women, although they remain in the low range. Insulin resistance as well as altered blood lipids and cytokines are observed when circulating estrogen levels are high within that range, but these differences are explained by concomitant variation in total adiposity

Androgens and body fat distribution

The sexual dimorphism in human body fat distribution suggests a causal role for sex hormones. This is of particular importance when considering the role of excess visceral adipose tissue accumulation as a critical determinant of obesity‐related cardiometabolic alterations. Scientific literature on the modulation of body fat distribution by androgens in humans is abundant, remarkably inconsistent and difficult to summarize. We reviewed relevant literature on this topic, with a particular emphasis on androgen replacement, androgen effects on selected parameters of adipose tissue function and adipose tissue steroid‐converting enzymes. In men, low androgenic status mostly reflected by reduced total testosterone is a frequent feature of visceral obesity and the metabolic syndrome. Regarding testosterone therapy, however, studies must be appreciated in the context of current controversies on their cardiovascular effects. Analyses of available studies suggest that decreases in waist circumference in response to testosterone are more likely observed in men with low levels of testosterone and high BMI at study onset. In women with androgen excess, higher testosterone and free testosterone levels are fairly consistent predictors of increased abdominal and/or visceral adipose tissue accumulation, which is not the case in nonhyperandrogenic women. Regarding mechanisms, androgens decrease adipogenesis and markers of lipid storage in vitro in men and women. Evidence also suggest that local steroid transformations by adipose tissue steroid‐converting enzymes expressed in a depot‐specific fashion may play a role in androgen‐mediated modulation of body fat distribution. Accumulating evidence shows that androgens are critical modulators of body fat distribution in both men and women

BPD-DS in the elderly

Background : Biliopancreatic diversion with duodenal switch (BPD-DS) is one of the most effective surgical approaches for the treatment of severe obesity. Objective : The objective of this study is to compare perioperative complications and long-term results of open BPD-DS in elderly versus younger patients. Methods : All patients aged 60 years and above who underwent a primary open BPD-DS in our center were selected (n = 105). Patients were matched 1:1 for sex, BMI, the presence of type 2 diabetes (T2DM), and year of surgery with a group of younger patients (aged ≤55 years). Results : The mean age of the patients was 62.3 ± 2.0 vs. 40.4 ± 7.0 years (p ≤ 0.0001). Initial BMI and prevalence of T2DM were similar in both groups, at 50.9 kg/m2 and 57 %, respectively. Mean operative time (178.6 ± 46.7 vs. 162.5 ± 39.9 min, p = 0.01), hospital stay (10.2 ± 8.3 vs. 6.3 ± 1.5 days, p = 0.0001), and blood loss (593 ± 484 vs. 474 ± 241 ml, p = 0.05) were significantly higher in elderly patients. No difference in 30-day mortality rate was observed (0.9 % in each group). There was no significant difference in major complication rate (16.2 vs. 8.6 %, p = 0.09). At a mean follow-up of 7.1 ± 4.1 years, excess weight loss (67.6 ± 19.2 vs. 72.7 ± 20.7 %, p = 0.06) and BMI (32.2 ± 5.7 vs. 30.8 ± 6.6 kg/m2, p = 0.15) were not significantly different. No significant difference was observed between the two groups for the resolution of T2DM (p = 0.53) and obstructive sleep apnea (p = 0.44). Conclusions : Open BPD-DS is associated with similar long-term benefits in elderly and younger patients, in terms of weight loss and resolution or improvement of obesity-related comorbidities. Perioperative complications might be more frequent in the elderly population, but this was not associated with increased mortality

Circulating steroid levels as correlates of adipose tissue phenotype in premenopausal women

Background: Obesity-related alterations in the circulating steroid hormone profile remain equivocal in women. Our objective was to identify circulating steroid levels that relate to increased adiposity and altered adipose phenotype in premenopausal women. Materials and methods: In a sample of 42 premenopausal women (age 46±3 years; BMI 27.1±4.2 kg/m2 ), 19 plasma steroids were quantified by ESI-LC-MS/MS. Body composition and fat distribution were assessed by dual-energy X-ray absorptiometry and computed tomography, respectively. Markers of adipose tissue function including adipocyte size distributions, radiological attenuation, and macrophage infiltration were also analyzed in surgically obtained visceral and subcutaneous fat samples. Results: Many negative correlations were observed between adiposity measurements such as BMI, body fat percentage or total abdominal adipose tissue area and plasma levels of androstenedione (r=-0.33 to -0.39, p≤0.04), androsterone (r=-0.30 to -0.38, p≤0.05) and plasma levels of steroid precursor pregnenolone (r=-0.36 to -0.46, p≤0.02). Visceral adipocyte hypertrophy was observed in patients with low pregnenolone concentrations (p<0.05). Visceral adipose tissue radiologic attenuation, a potential marker of adipocyte size, was also positively correlated with pregnenolone levels (r=0.33, p<0.05). Low levels of pregnenolone were related to increased number of macrophages infiltrating visceral and subcutaneous adipose tissue (p<0.05). Conclusion: Plasma levels of androgens and their precursors are lower in women with increased adiposity and visceral adipocyte hypertrophy. Low circulating pregnenolone concentration may represent a marker of adipose tissue dysfunction