Type-2 Familial Partial Lipodystrophy (FPLD2), a rare lipodystrophy caused by
mutations, is characterized by a loss of subcutaneous fat from the trunk and limbs and excess accumulation of adipose ...tissue in the neck and face. Several studies have reported that the mineralocorticoid receptor (MR) plays an essential role in adipose tissue differentiation and functionality. We previously showed that brown preadipocytes isolated from a FPLD2 patient's neck aberrantly differentiate towards the white lineage. As this condition may be related to MR activation, we suspected altered MR dynamics in FPLD2. Despite cytoplasmic MR localization in control brown adipocytes, retention of MR was observed in FPLD2 brown adipocyte nuclei. Moreover, overexpression of wild-type or mutated prelamin A caused GFP-MR recruitment to the nuclear envelope in HEK293 cells, while drug-induced prelamin A co-localized with endogenous MR in human preadipocytes. Based on in silico analysis and in situ protein ligation assays, we could suggest an interaction between prelamin A and MR, which appears to be inhibited by mineralocorticoid receptor antagonism. Importantly, the MR antagonist spironolactone redirected FPLD2 preadipocyte differentiation towards the brown lineage, avoiding the formation of enlarged and dysmorphic lipid droplets. Finally, beneficial effects on brown adipose tissue activity were observed in an FPLD2 patient undergoing spironolactone treatment. These findings identify MR as a new lamin A interactor and a new player in lamin A-linked lipodystrophies.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
ObjectiveRegeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within liver and adipose tissue may be of pathophysiological importance in obesity and the metabolic syndrome. ...single nucleotide polymorphisms (SNPs) in HSD11B1, the gene encoding 11β-HSD1, have been associated with type 2 diabetes and hypertension in population-based cohort studies, and with hyperandrogenism in patients with the polycystic ovary syndrome (PCOS). However, the functional consequences of these SNPs for in vivo 11β-HSD1 expression and activity are unknown.MethodsWe explored associations of well-characterised hormonal and metabolic phenotypes with two common SNPs (rs846910 and rs12086634) in HSD11B1 in 600 women (300 with PCOS) and investigated 11β-HSD1 expression and activity in a nested study of 40 women from this cohort.ResultsHSD11B1 genotypes (as single SNPs and as the combination of the two minor allele SNPs) were not associated with PCOS. Women who were heterozygous for rs846910 A and homozygous for rs12086634 T (GA, TT genotype) had a higher risk of metabolic syndrome, regardless of the diagnosis of PCOS (odds ratio in the whole cohort=2.77 (95% confidence interval (CI) 1.16–6.67), P=0.023). In the nested cohort, women with the GA, TT genotype had higher HSD11B1 mRNA levels in adipose tissue, and higher rates of appearance of cortisol and d3-cortisol (16.1±0.7 nmol/min versus 12.1±1.1, P=0.044) during 9,11,12,12-2H4-cortisol (d4-cortisol) steady-state infusion.ConclusionsWe conclude that, in a population of Southern European Caucasian women with and without PCOS, alleles of HSD11B1 containing the two SNPs rs846910 A and rs12086634 T confer increased 11β-HSD1 expression and activity, which associates with the metabolic syndrome.
Abstract Objective The endocannabinoid system hypertonicity features obesity. Excess circulating 2-arachidonoylglycerol was variously associated with obesity-related metabolic impairment; however, ...unstandardized experimental and analytical settings have clouded its usefulness as a dysmetabolism biomarker. We aimed at assessing the influence of body mass index (BMI), menopause in women, and aging in men on 2-arachidonoylglycerol relationship with metabolic parameters. Methods Adult, unmedicated women (premenopausal (preMW): n = 103; menopausal (MW): n = 81) and men (n = 144) were stratified in normal weight (NW; BMI: 18.5–24.9 kg/m2 ), overweight (OW; BMI: 25.0–29.9 kg/m2 ), and obese (OB; BMI ≥ 30.0 kg/m2 ) classes. Anthropometric and metabolic parameters were determined. Plasma 2-arachidonoylglycerol was measured by a validated liquid chromatography-mass spectrometry assay. Results 2-arachidonoylglycerol level was raised by menopause (P < 0.001) and by obesity in preMW (P < 0.001) and in men (P = 0.019). In the overall cohorts, 2-arachidonoylglycerol displayed BMI-independent relationships with dyslipidemia (preMW, MW and men), insulin resistance (MW and men), and hypertension (men), but not with waist circumference. Within preMW BMI classes, 2-arachidonoylglycerol correlations were found with triglycerides (P = 0.020) and total cholesterol (TC; P = 0.040) in OB women. In MW, 2-arachidonoylglycerol correlation with triglycerides was found in NW (P = 0.001) and OW (P = 0.034), but not in OB class. Moreover, we found 2-arachidonoylglycerol correlations with TC (P = 0.003), glucose (P < 0.001), and HOMA-IR (P = 0.035) specific for NW MW class. In men, 2-arachidonoylglycerol correlated with triglycerides in NW, OW (both P < 0.001), and OB (P = 0.029), with SBP (P = 0.023) and diastolic BP (DBP; P = 0.048) in OB, and with TC (P < 0.001) in OW class. In NW class 2-arachidonoylglycerol correlations were found with insulin (P = 0.003) and HOMA-IR (P = 0.001), both enhanced by aging (both P = 0.004), and with glucose (P = 0.015) and HDL (P = 0.004). Conclusions Plasma 2AG is a biomarker of clustering metabolic dysfunctions, especially in lean men and menopausal women, and could be of help in identifying subjects with elevated cardiometabolic risk despite a healthy anthropometric appearance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The diagnosis of polycystic ovary syndrome (PCOS) remains challenging due to limited data regarding normative cut-offs for the diagnostic features in different subpopulations. We aim to conduct a ...systematic review, build a comprehensive repository of de-identified individual participant data (IPD), and define normative ranges and diagnostic cut-offs for all PCOS diagnostic features. We will conduct a systematic search of MEDLINE and EMBASE databases for studies that assessed PCOS diagnostic features in unselected women. Two reviewers will assess eligibility and perform quality appraisal. Authors of included studies will be invited to contribute IPD. Primary variables include directly assessed modified Ferriman Gallwey (mFG) scores; menstrual cycle lengths; follicle number per ovary (FNPO), ovarian volume (OV), anti-Müllerian hormone (AMH); circulating androgens, including total testosterone (TT), free testosterone, bioavailable testosterone, free androgen index (FAI), androstenedione (A4), and dehydroepiandrosterone sulphate (DHEAS). Normative ranges and cut-offs will be defined using cluster analysis. Monash University Human Research Ethics Committee granted ethical approval (26938/0 1/12/2020), all IPD will be de-identified and primary studies have ethical approval from their institutional ethics committees. Findings will clarify distinction between PCOS and non-PCOS populations, and inform the update of the international evidence-based guidelines for the assessment and management of PCOS.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Polycystic ovary syndrome (PCOS) is considered a risk factor for the development of type 2 diabetes mellitus (T2DM). However, which is the most appropriate way to evaluate dysglycemia in ...women with PCOS and who are at increased risk are as yet unclear. Aim of the study To determine the prevalence of T2DM, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in PCOS women and potential factors to identify those at risk. Subjects and methods The oral glucose tolerance test (OGTT), biochemical/hormonal profile, and ovarian ultrasound data from 1614 Caucasian women with PCOS and 362 controls were analyzed in this cross-sectional multicenter study. The data were categorized according to age and BMI. Results Dysglycemia (T2DM, IGT, and IFG according to World Health Organization criteria) was more frequent in the PCOS group compared to controls: 2.2% vs 0.8%, P = 0.04; 9.5% vs 7.4%, P = 0.038; 14.2% vs 9.1%, P = 0.002, respectively. OGTT was essential for T2DM diagnosis, since in 88% of them basal glucose values were inconclusive for diagnosis. The presence of either T2DM or IFG was irrespective of age (P = 0.54) and BMI (P = 0.32), although the latter was associated with IGT (P = 0.021). There was no impact of age and BMI status on the prevalence of T2DM or IFG. Regression analysis revealed a role for age, BMI, fat deposition, androgens, and insulin resistance for dysglycemia. However, none of the factors prevailed as a useful marker employed in clinical practice. Conclusions One-third of our cohort of PCOS women with either T2DM or IGT displayed normal fasting glucose values but without confirming any specific predictor for dysglycemic condition. Hence, the evaluation of glycemic status using OGTT in all women with PCOS is strongly supported.
PCOS is not only the most frequent cause of oligomenorrhea in young women, but also a metabolic disorder characterized by insulin resistance, glucose intolerance, dyslipidemia, and obesity, ...especially the visceral phenotype. PCOS represents a broad spectrum of endocrine and metabolic alterations which change with age and with increasing adiposity. In fact, during adolescence and youth the predominant clinical manifestations of PCOS are menstrual abnormalities, hirsutism and acne, whereas in peri-menopausal and post-menopausal periods metabolic disorders and an increased risk for cardiovascular diseases prevail. The pathogenetic links between PCOS and metabolic or cardiovascular complications are still debated. However, recent evidence has been focused on a condition of low-grade chronic inflammation as a potential cause of the long-term consequence of the syndrome.
In this review we describe the state of low-grade inflammation observed in PCOS. In addition, we hypothesize the potential mechanisms responsible for the generation of this inflammatory state and the role played by low-grade inflammation in linking hyperandrogenism and insulin resistance with the metabolic and cardiovascular long-term complications of the syndrome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Prelamin A processing impairment is a common feature of a restricted group of rare genetic alterations/disorders associated with a wide range of clinical phenotypes. Changes in histone ...posttranslational modifications, alterations in non-histone chromatin proteins and chromatin disorganization have been specifically linked to impairment of specific, distinct prelamin A processing steps, but the molecular mechanism involved in these processes is not yet understood . In this study, we show that the accumulation of wild-type prelamin A detected in restrictive dermopathy (RD), as well as the accumulation of mutated forms of prelamin A identified in familial partial lipodystrophy (FPLD) and mandibuloacral dysplasia (MADA), affect the nuclear localization of barrier-to-autointegration factor (BAF), a protein able to link lamin A precursor to chromatin remodeling functions. Our findings, in accordance with previously described results, support the hypothesis of a prelamin A involvement in BAF nuclear recruitment and suggest BAF-prelamin A complex as a protein platform usually activated in prelamin A-accumulating diseases. Finally, we demonstrate the involvement of the inner nuclear membrane protein emerin in the proper localization of BAF-prelamin A complex.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Hirsutism is a common medical complaint among women of reproductive age, and it affects the majority of women with the polycystic ovary syndrome (PCOS). Increased rate of androgen production and its ...availability in tissue represent the main pathophysiological mechanisms responsible for hirsutism. In addition, androgens may be generated de novo in the hair follicle; therefore, circulating androgen levels do not quantify the real exposure of the hair follicle to androgens, as a quota is locally generated. Hirsutism is a clinical sign and not a disease in itself; its presence does not therefore necessarily require treatment, particularly in mild-to-moderate forms, and when an affected woman does not worry about it. Physicians should decide whether hirsutism is to be treated or not by evaluating not only the severity of the phenomenon but also the subjective perception of the patient, which does not necessarily correspond to the true extent of hair growth. In any case, a physician should manage a woman with hirsutism only on the basis of a diagnosis of the underlying cause, and after a clear explanation of the efficacy of each therapeutic choice. Cosmetic procedures and pharmacological intervention are commonly used in the treatment of hirsutism and are discussed in this paper. Importantly, there are different phenotypes of women with hirsutism and PCOS that may require specific attention in the choice of treatment. In particular, when obesity is present, lifestyle intervention should be always considered, and if necessary combined with pharmacotherapy.
Context: Insulin-like factor 3 (INSL3), a member of the relaxin-insulin family, is produced in the Leydig cells and at reduced levels in ovarian theca interna cells of antra follicles as well as in ...the corpora lutea and ovarian stroma. Among the factors potentially involved in the stimulation of gonadal expression of INSL3, recent data obtained in rats show an important role of LH. Ovaries from most women affected by polycystic ovary syndrome (PCOS) are characterized by hyperplasia of the theca interna and of cortical stroma and by an increased number of small antral follicles, and the majority of women with PCOS, particularly normal-weight subjects, have LH levels that are above the normal range.
Objective: The objective of this study was to investigate INSL3 circulating levels in both normal-weight and overweight-obese PCOS women and the association of INSL3 with gonadotropin and androgenic pattern and with ovarian morphology.
Design: This was a controlled study.
Setting: The study took place at an academic hospital.
Participants: The participants included 44 PCOS patients (22 normal-weight and 22 overweight-obese) and 44 controls comparable for age and body weight.
Main Outcome Measures: The main outcome measures included INSL3 serum concentrations, measured by RIA, in PCOS patients and controls and their correlation with clinical and biochemical phenotype and with ovarian morphology.
Results: INSL3 serum concentrations were significantly higher in PCOS patients with respect to controls (P = 0.003), particularly in normal-weight (P = 0.001) but not in overweight-obese (P = 0.312) PCOS patients. INSL3 serum concentrations were positively correlated with total and free testosterone and with LH levels in all women (total testosterone, P < 0.001; free testosterone, P = 0.001; LH, P = 0.002) as well as in PCOS patients (total testosterone, P = 0.024; free testosterone, P = 0.045; LH, P = 0.049). Moreover, in the PCOS group, INSL3 levels were related to a greater 17OH-progesterone response to buserelin (P = 0.015), an index of ovarian hyperandrogenism. Finally, in PCOS women, INSL3 levels were positively correlated with ovarian follicle number (P = 0.028).
Conclusions: INSL3 could be considered a new circulating hormone related to LH-dependent ovarian hyperandrogenism, particularly in normal-weight PCOS women.
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