Subcutaneous Adipose Tissue In Women Research Articles

Differences in metabonomic profiles of abdominal subcutaneous adipose tissue in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that often coexists with a metabolic disorder. Studies have demonstrated that the malfunction of adipose tissue, particularly abdominal adipose tissue, could exacerbate reproductive and metabolic problems in PCOS patients. Adipose tissue-secreted signaling mediators (e.g., lipids and metabolites) would then interact with other body organs, including the ovary, to maintain the systemic equilibrium. In this study, we examined adipose samples from PCOS patients and unaffected individuals using a liquid chromatography-mass spectrometry-based metabonomics approach (LC-MS/MS). PCOS biomarkers were selected using multivariate statistical analysis. Our pathway analysis revealed that these differential metabolites could be engaged in inflammatory diseases and mitochondrial beta-oxidation. We further developed an in vitro PCOS cell model to examine the effects of hyperandrogenism on granulosa cells and related metabolic disorders. We noted that isoleucine recovered the promotive effect on cell apoptosis, inhibitory effect on cell proliferation, sex hormone secretion, and mitochondrial function induced by dehydroepiandrosterone. Our gas chromatography-mass spectrometry targeted analysis (GC-MS/MS) revealed that isoleucine was significantly decreased in PCOS patients. Based on these results, we speculate that metabolome alterations are vital in ameliorating PCOS symptoms. This may be a novel therapeutic target for PCOS treatment. Our study provides preliminary evidence that these findings will enhance our ability to accurately diagnose and intervene in PCOS.

Transcriptional and DNA Methylation Signatures of Subcutaneous Adipose Tissue and Adipose-Derived Stem Cells in PCOS Women

Polycystic ovary syndrome (PCOS) is often associated with metabolic syndrome features, including central obesity, suggesting that adipose tissue (AT) is a key organ in PCOS pathobiology. In this study, we compared both abdominal (ABD) and gluteofemoral (GF) subcutaneous AT in women with and without PCOS. ABD and GF subcutaneous ATs from PCOS and BMI/WHR-matched control women were analyzed by RT-qPCR, FACS and histology. ABD and GF adipose-derived stem cell (ASC) transcriptome and methylome were analyzed by RNA-seq and DNA methylation array. Similar to the control group with abdominal obesity, the GF AT of PCOS women showed lower expression of genes involved in lipid accumulation and angiogenesis compared to ABD depot. FACS analysis revealed an increase in preadipocytes number in both AT depots from PCOS. Further pathway analysis of RNA-seq comparisons demonstrated that the ASCs derived from PCOS are pro-inflammatory and exhibit a hypoxic signature in the ABD depot and have lower expression of adipogenic genes in GF depot. We also found a higher CpG methylation level in PCOS compared to control exclusively in GF-ASCs. Our data suggest that ASCs play an important role in the etiology of PCOS, potentially by limiting expansion of the healthy lower-body AT.

Gluteal subcutaneous adipose tissue in women of different ages and body mass index observed by magnetic resonance imaging.

Magnetic resonance imaging (MRI) is a recognized method to assess the morphological characteristics of subcutaneous adipose tissue (SAT). This study aimed to assess objectively different characteristics of SAT of women with different ages and body mass index (BMI) using MRI. Retrospective, observational study. Pelvic-MRI exams of 133 women aged between 15 and 80years, with BMI 16-30kg/m2 were assessed. There was a moderate positive correlation between the total fat thickness and the BMI (r=0.64; p<0.0001) considering the entire sample. Within the different age groups, strong positive correlation was observed for age groups 15 to 30years (r=0.76; p<0.0001) and 46 to 60years (r=0.75; p<0.0001), and moderate positive correlation in the others (r=0.61; p<0.0001 [31-45years] and r=0.53; p<0.0001 [>61years-old]). There was no correlation between age and fat layer thickness. Correlation between deep fat layer thickness and BMI showed similar pattern to that of the total fat layer. Within the different BMI groups, SAT thickness tends to decrease with aging in patients with low BMI. Inside each age group, the average thickness of the total fat layer increases according to BMI. The results suggest that BMI influences the thickness of SAT throughout life and how SAT changes with age in patients with different BMI. In patients with moderate BMI, the thickness of SAT remains stable.

Glucose transporter 4 mRNA expression in subcutaneous adipose tissue of women with PCOS remains unchanged despite metformin withdrawal: is there a cellular metabolic treatment legacy effect?

Metformin induces GLUT-4 mRNA expression in insulin target tissues in PCOS. It is unclear how long this impact is sustained after withdrawal of metformin. We aimed to compare the effect of metformin withdrawal on GLUT-4 mRNA expression in subcutaneous adipose tissue after prior short (ST, 1 year, N = 11) and long term (LT, at least 3 years, N = 13) treatment in obese PCOS women. At baseline and 6 months after withdrawal, biopsy of subcutaneous adipose tissue followed by quantitative PCR analysis was performed to determine GLUT-4 mRNA expression. We found no time/effect differences in GLUT-4 mRNA expression in ST (2-dCt at baseline 0.42 (0.16-0.48) vs 2-dCt after 6 months 0.31 (0.22-0.56), p = 0.594) and no time/effect difference in LT group (2-dCt at baseline 0.24 (0.14-0.39) vs 2-dCt after 6 months 0.25 (0.20-0.38), p = 0.382). There was also no difference in GLUT-4 mRNA expression between both groups at baseline and after 6 months. In summary, 6 months after metformin withdrawal, GLUT-4 mRNA expression in subcutaneous adipose tissue remained stable, regardless of the prior treatment duration.

Association of Periaortic Fat and Abdominal Visceral Fat with Coronary Artery Atherosclerosis in Chinese Middle Aged and Elderly Patients Undergoing Computed Tomography Coronary Angiography.

Background and Aims:Coronary artery disease (CAD) is usually caused by atherosclerosis, which is associated with general obesity and stronger associations with localized ectopic fat depots have been reported. We measured body ectopic fat distribution in Chinese patients to determine the association with coronary artery atherosclerosis (CA).Methods:Patients undergoing coronary computed tomography angiography (CCTA) who agreed to participate in the study (n = 750, 50.4% men, mean age 64.8 years) had cardiovascular disease and risk assessment. Body ectopic fat depots were measured from CT and their association with CA, determined from CCTA, was evaluated by univariate and multivariate logistic regression models.Results:CAD with CA (CAD-CA) was present in 57.2% of participants with CAD of moderate/severe CA (CAD-msCA) present in 23.5% and both were significantly more frequent in men than in women. Overall, men had greater body mass index (BMI) but there was no difference in waist circumference (WC) between genders. However, significantly higher visceral adipose tissue (VAT) and periaortic fat volume (PAFV) were observed in men, whereas women had significantly higher abdominal subcutaneous adipose tissue (SAT). With increasing age, there was a significant decline in BMI, WC and SAT in men, but a significant increase of WC and VAT, PAFV and epicardial fat volume (EFV) in women. A high proportion of non-calcified plaques was observed in CAD-CA, 55.3% in CAD of minimal/mild CA (CAD-mmCA) with 38.7% exclusively non-calcified plaques, and 59.7% in CAD-msCA with multiple type plaques containing non-calcified ones. Multivariate logistic regression showed a significant association of PAFV with CAD-CA and CAD-msCA that was independent of general obesity and clinical risk factors, and independent of abdominal obesity in the highest PAFV quartile patients. VATA was associated with an increased prevalence of CAD-msCA in the patients in the upper 2 VATA quartiles that was independent of clinical risk factors and both general and abdominal obesity.Conclusions:We found age and gender differences of body ectopic fat distribution in Chinese patients with higher VAT and PAFV in men and higher SAT in women. With increased age, there was a decline of WC and SAT in men but not in women and an increase in WC, VAT and PAFV in women but not in men. PAFV was significantly associated with overall CAD-CA and CAD-msCA, while VAT was associated with CAD-msCA.

1589-P: Testosterone (T) in Early Puberty Predicts Visceral (VAT) and Subcutaneous Adipose Tissue (SAT) in the EPOCH (Exploring Perinatal Outcomes among Children) Cohort

Among adults, higher T predicts lower VAT in men and higher VAT in women, and higher E2 predicts greater SAT in women. The degree to which the association between adiposity and sex steroids is bidirectional is controversial. Using data from a cohort of adolescents, we examined whether sex steroid levels in early puberty influenced VAT and SAT deposition in adolescents. EPOCH participants (n=418, 209 girls and 209 boys) underwent sex steroid measures at visit 1 (mean age 10 years) and magnetic resonance imaging (MRI) assessments of VAT and SAT at visit 1 and visit 2 (mean age 17 years). Using mixed models, we examined whether T and E2 at visit 1 were associated with overall VAT and SAT levels from visit 1 to visit 2. Models adjusted for maternal education and income as well as children’s race, pubertal status, caloric intake, physical activity levels, insulin, leptin, and MRI-measured hepatic fat fraction. Among girls, each unit increase in T was associated with a higher overall VAT (0.16, 95% confidence interval [CI] 0.04, 0.28) and SAT (0.33, 95% CI 0.33, 1.52) levels. Each unit increase in E2 was associated with overall higher SAT (0.56, 95% CI 0.28, 0.83) levels. Among boys, undetectable T was associated with higher VAT (5.12, 95% CI 1.90, 8.36) and lower SAT (-18.85, 95% CI -36.23, -1.46) levels. We conclude that endogenous T and E2 during the pubertal transition significantly influence adolescent adipose tissue deposition in both boys and girls. Future investigations should examine how the use of exogenous sex hormones impacts adipose tissue deposition during this critical period. Additional follow-up is needed to determine how adolescent fat deposition impacts subsequent glucose tolerance in early adulthood. Disclosure C. Kim: Research Support; Spouse/Partner; Apple. K.K. Harrall: None. D.H. Glueck: None. D. Dabelea: None. Funding National Institutes of Health (R01DK068001)

Intermittent fasting increases energy expenditure and promotes adipose tissue browning in mice.

Intermittent fasting (IF) may limit metabolic adaptations that reduce energy expenditure, potentially by stimulating white adipose tissue (WAT) browning. The aim of this study was to examine the effects of 8 wk of IF on energy metabolism and markers of WAT browning in lean and diet-induced obese mice and in women who were overweight or obese. Male C57 BL/6 J mice were fed chow or a high-fat diet (HFD; 43%) for 8 wk before undergoing IF (3 non-consecutive d/wk) for an additional 8 wk. Food intake, energy expenditure, and inguinal and gonadal fat pads were collected in fed or fasted conditions (22 h, IF mice only). Subcutaneous adipose tissue (SAT) was also collected at baseline, and after 8 wk of IF (in the fed state, and after a 24-h fast), in women with overweight or obesity. Uncoupling protein 1 (UCP1) was assessed by quantitative real-time polymerase chain reaction (mice and humans) and immunohistochemistry (mice). IF reduced body weight and energy intake in HFD fed mice and reduced gonadal and inguinal fat pad weights in both diet groups. IF increased energy expenditure, meal number, Ucp1 mRNA levels in inguinal and gonadal fat depots, and UCP1 protein in inguinal fat in both diet groups on fed days. In women, IF reduced body weight and fat mass, but did not alter UCP1mRNA levels. IF increased energy expenditure and promoted WAT browning in mice but did not alter UCP1 mRNA levels in SAT in women.

Metabolic Syndrome is Associated with Ceramide Accumulation in Visceral Adipose Tissue of Women with Morbid Obesity.

ObjectiveAccelerated transmembrane transport of long‐chain fatty acids dependent on fatty acid transporters is responsible for lipid accumulation and, eventually, the development of metabolic syndrome. This study determined the content of lipids (ceramide [CER], diacylglycerol [DAG], triacylglycerol, and free fatty acid [FFA]) and the expression of fatty acid translocase (FAT/CD36) and plasma membrane fatty acid‐binding protein in visceral adipose tissue (VAT) and subcutaneous adipose tissue of women with morbid obesity without metabolic syndrome (MetSx−) or with metabolic syndrome (MetSx+) and compared the results with those of lean controls without metabolic syndrome.MethodsLipid content and fatty acid composition in each lipid subclass were estimated by gas liquid chromatography. For total, plasma membrane, and mitochondrial expression of fatty acid transporters, subfractionation with subsequent Western blot technique was used.ResultsA greater content of triacylglycerol in VAT of participants with obesity (MetSx−) was found. However, only the MetSx+ subjects had increased content of CER in VAT in relation to subcutaneous adipose tissue in MetSx+ and lean individuals. This was accompanied by increased total and membrane expression of FAT/CD36 in VAT in MetSx+ subjects. Accordingly, mitochondrial expression of FAT/CD36 and plasma membrane fatty acid‐binding protein was decreased in both groups of subjects with obesity.ConclusionsMetabolic syndrome is associated with the accumulation of CER in VAT, possibly related to increased FAT/CD36 protein expression.

Excess androgen production in subcutaneous adipose tissue of women with polycystic ovarian syndrome is not related to insulin or LH.

The purpose of this study was to investigate androgen production and the role of insulin and LH in its regulation in subcutaneous adipose tissue (SAT) of women with polycystic ovarian syndrome (PCOS). Protein and mRNA expression of androgen synthesis enzymes (Cytochrome P450 17A1 [CYP17A1] and Aldo-keto reductase 1C3 [AKR1C3]) were measured in SAT biopsies from women with PCOS, diagnosed according to the Rotterdam criteria (n=15) and healthy controls (n=15). Cultured mature adipocytes (differentiated from SAT biopsies) were treated with insulin ± phosphoinositol-3-kinase inhibitor (LY294002) or LH ± insulin. CYP17A1 and AKR1C3 mRNA expression and testosterone concentrations were measured in treated and untreated adipocyte cultures. AKR1C3 mRNA was significantly (P<0.001) greater in PCOS versus non-PCOS SAT, but CYP17A1 was not significantly different between the two groups. AKR1C3 and CYP17A1 protein expression was not significantly different in PCOS versus non-PCOS SAT. In untreated adipocyte cultures, CYP17A1, AKR1C3 and testosterone levels were significantly higher in the PCOS versus the non-PCOS groups. Addition of insulin increased AKR1C3 mRNA and testosterone levels, but not CYP17A1 mRNA in non-PCOS with no effect on PCOS adipocytes. The stimulatory effects of insulin were not inhibited by LY294002. Addition of LH increased CYP17A1, AKR1C3 and testosterone in non-PCOS adipocytes with no effect in PCOS adipocytes. In conclusion, SAT of women with PCOS produces excess androgen, which may contribute to PCOS-related hyperandrogenaemia. This SAT androgen excess is independent of obesity and is not directly stimulated by insulin or LH.

SUBCUTANEOUS ADIPOSE TISSUE IN FEMALE PATIENTS WITH IRON DEFICIENCY ANEMIA AND OBESE WOMEN DOES NOT DIFFER IN THE EXPRESSION OF IKBΑ*

Prerequisites and objective: Abdominal obesity is a common metabolic disease characterized by excessive accumulation of white adipose tissue, with excessive production of inflammatory mediators that activate transcriptional nuclear factors, in particular the nuclear factor kB. Hepcidin is the main hormone in the systemic regulation of iron. Its expression increases with elevated level of pro-inflammatory cytokines, as a result of which the concentration of iron in the blood plasma decreases, which reliably results in the activation of NF-kB. Therefore, the aim of the research was to determine the level of expression of ІКβα in subcutaneous adipose tissue in iron deficiency anemia concurrent with obesity. Methods: The study included 40 female women. Hemogram parameters, parameters of iron metabolism (serum iron, ferritin, hepcidin, total iron binding ability of serum, saturation of transferrin by iron) in serum and level of expression of the IkBα gene in subcutaneous adipose tissue were evaluated. Research results. The examined women had an average age of 40.3 ± 7.59 years. In the distribution of patients due to the cause and degree of severity of IDA, there was no reliable difference between the groups. The control group consisted of 10 obese women without IDA. Expression of IkBα by subcutaneous adipose tissue in female patients with IDA with and without obesity compared with the control group did not display a significant difference between the groups (p &lt;0.05). In the course of correlation analysis, the expression of IkBα by subcutaneous adipose tissue to BMI, iron and hemogram rates did not have a correlated significance. Conclusion. Subcutaneous adipose tissue in women with iron deficiency anemia with and without obesity compared with obese women has no difference in expression of IkBα.

Differences in Upper and Lower Body Adipose Tissue Oxygen Tension Contribute to the Adipose Tissue Phenotype in Humans.

Upper and lower body adipose tissue (AT) exhibits opposing associations with obesity-related cardiometabolic diseases. Recent studies have suggested that altered AT oxygen tension (pO2) may contribute to AT dysfunction. Here, we compared in vivo abdominal (ABD) and femoral (FEM) subcutaneous AT pO2 in women who are overweight and have obesity, and investigated the effects of physiological AT pO2 on human adipocyte function. ABD and FEM subcutaneous AT pO2 and AT blood flow (ATBF) were assessed in eight [BMI (body mass index) 34.4 ± 1.6 kg/m2] postmenopausal women who were overweight with obesity and impaired glucose metabolism. ABD and FEM AT biopsy specimens were collected to determine adipocyte morphology and AT gene expression. Moreover, the effects of prolonged exposure (14 days) to physiological AT pO2 on adipokine expression/secretion, mitochondrial respiration, and glucose uptake were investigated in differentiated human multipotent adipose-derived stem cells. AT pO2 was higher in ABD than FEM AT (62.7 ± 6.6 vs 50.0 ± 4.5 mm Hg, P = 0.013), whereas ATBF was comparable between depots. Maximal uncoupled oxygen consumption rates were substantially lower in ABD than FEM adipocytes for all pO2 conditions. Low physiological pO2 (5% O2) decreased proinflammatory gene expression, increased basal glucose uptake, and altered adipokine secretion in ABD and FEM adipocytes. We demonstrated for the first time, to our knowledge, that AT pO2 is higher in ABD than FEM subcutaneous AT in women who are overweight/with obesity, partly due to a lower oxygen consumption rate in ABD adipocytes. Moreover, low physiological pO2 decreased proinflammatory gene expression and improved the metabolic phenotype in differentiated human adipocytes, whereas more heterogeneous effects on adipokine secretion were found.

Tissue Sodium Content is Elevated in the Skin and Subcutaneous Adipose Tissue in Women with Lipedema.

ObjectiveTo test the hypothesis that tissue sodium and adipose content are elevated in patients with lipedema; if confirmed, this could establish precedence for tissue sodium and adipose content representing a discriminatory biomarker for lipedema.MethodsParticipants with lipedema (n=10) and control (n=11) volunteers matched for biological sex, age, body-mass-index, and calf circumference were scanned noninvasively with 3.0T sodium and conventional proton MRI. Standardized tissue sodium content was quantified in skin, subcutaneous adipose tissue (SAT), and calf muscle. Dixon MRI was employed to quantify tissue fat and water volumes of the calf. Nonparametric statistical tests were applied to compare regional sodium content and fat-to-water volume ratio between groups (significance: two-sided p≤0.05).ResultsSkin (p=0.01) and SAT (p=0.04) sodium content were elevated in lipedema (skin: 14.9±2.9 mmol/L; SAT: 11.9±3.1 mmol/L) relative to control (skin: 11.9±2.0 mmol/L; SAT: 9.4±1.6 mmol/L) participants. Relative fat volume in the calf was elevated in lipedema (1.2±0.48 ratio) relative to control (0.63±0.26 ratio, p<0.001) participants. Skin sodium content was directly correlated with fat-to-water volume ratio (Spearman’s-rho=0.54, p=0.01).ConclusionsInternal metrics of tissue sodium and adipose content are elevated in patients with lipedema potentially providing objective imaging-based biomarkers for differentially diagnosing the under-recognized condition of lipedema from obesity.

Sex differences in regulation of adipose tissue

This review is focused on sex differences in regulation of adipose tissue. The heterogeneity of structural and functional features as well as differences in regulation of visceral and subcutaneous adipose tissues are discussed. It was shown that estrogens have pleiotropic protective impact by direct influence on adipocytes and indirect effect through hypothalamic regulation of sympathetic innervation of adipose tissue, modulating lipolysis, proliferation of preadipocytes and hyperplasia, as well as transformation of white adipocytes to brown ones. The high volume of subcutaneous adipose tissue in women is determined by the effects of estrogens and is the main factor that provides female special resistance to metabolic diseases. In general, an increase of subcutaneous fat is more favorable for metabolic profile. In contrast, visceral fat depot is associated with insulin resistance and the development of associated pathology.

Erratum: The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation.

Objective This study characterized the kynurenine pathway (KP) in human obesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue. Methods Tryptophan and KP metabolite levels were measured in serum of individuals from the D.E.S.I.R. cohort (case-cohort study: 212 diabetic, 836 randomly sampled) and in women with obesity, diabetic or normoglycemic, from the ABOS cohort (n = 100). KP enzyme gene expressions were analyzed in omental and subcutaneous adipose tissue of women from the ABOS cohort, in human primary adipocytes and in monocyte-derived macrophages. Results In the D.E.S.I.R. cohort, kynurenine levels were positively associated with body mass index (BMI) (P = 4.68 × 10) and with a higher HOMA2-IR insulin resistance index (P = 6.23 × 10). The levels of kynurenine, kynurenic acid, and quinolinic acid were associated with higher BMI (P < 0.05). The expression of several KP enzyme genes (indoleamine 2,3-dioxygenase 1 [IDO1], kynureninase [KYNU], kynurenine 3-monooxygenase [KMO], and kynurenine aminotransferase III [CCBL2]) was increased in the omental adipose tissue of women with obesity compared to lean (P < 0.05), and their expression was induced by proinflammatory cytokines in human primary adipocytes (P < 0.05), except for KMO that is not expressed in these cells. The expressions of IDO1, KYNU, KMO, and CCBL2 were higher in proinflammatory than in anti-inflammatory macrophages (P < 0.05). Conclusions In the context of obesity, the presence of macrophages in adipose tissue may contribute to diverting KP toward KMO activation.

Differences in In Vivo Cellular Kinetics in Abdominal and Femoral Subcutaneous Adipose Tissue in Women.

The accumulation of fat in upper-body (abdominal) adipose tissue is associated with obesity-related cardiometabolic diseases, whereas lower-body (gluteal and femoral) fat may be protective. Studies suggest physiological and molecular differences between adipose depots and depot-specific cellular mechanisms of adipose expansion. We assessed in vivo cellular kinetics in subcutaneous adipose tissue from the abdominal (scABD) and femoral (scFEM) depots using an 8-week incorporation of deuterium (2H) from 2H2O into the DNA of adipocytes and preadipocytes in 25 women with overweight or obesity. DNA synthesis rates denote new cell formation of preadipocytes and adipocytes in each depot. Formation of adipocytes was positively correlated to that of preadipocytes in the scABD and scFEM depots and was related to percent body fat in each depot. Notably, preadipocytes and adipocytes had higher formation rates in the scFEM depot relative to the scABD. This method to assess in vivo adipogenesis will be valuable to evaluate adipocyte kinetics in individuals with varying body fat distributions and degrees of metabolic health and in response to a variety of interventions, such as diet, exercise, or pharmacological treatment.

Characterization of visceral and subcutaneous adipose tissue transcriptome in pregnant women with and without spontaneous labor at term: implication of alternative splicing in the metabolic adaptations of adipose tissue to parturition.

The aim of this study was to determine gene expression and splicing changes associated with parturition and regions (visceral vs. subcutaneous) of the adipose tissue of pregnant women. The transcriptome of visceral and abdominal subcutaneous adipose tissue from pregnant women at term with (n=15) and without (n=25) spontaneous labor was profiled with the Affymetrix GeneChip Human Exon 1.0 ST array. Overall gene expression changes and the differential exon usage rate were compared between patient groups (unpaired analyses) and adipose tissue regions (paired analyses). Selected genes were tested by quantitative reverse transcription-polymerase chain reaction. Four hundred and eighty-two genes were differentially expressed between visceral and subcutaneous fat of pregnant women with spontaneous labor at term (q-value <0.1; fold change >1.5). Biological processes enriched in this comparison included tissue and vasculature development as well as inflammatory and metabolic pathways. Differential splicing was found for 42 genes [q-value <0.1; differences in Finding Isoforms using Robust Multichip Analysis scores >2] between adipose tissue regions of women not in labor. Differential exon usage associated with parturition was found for three genes (LIMS1, HSPA5, and GSTK1) in subcutaneous tissues. We show for the first time evidence of implication of mRNA splicing and processing machinery in the subcutaneous adipose tissue of women in labor compared to those without labor.

Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat.

BackgroundTo identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR).Subjects and MethodsSex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for BMI, and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2,513 subjects of European descent were available for the discovery phase. For replication, 2,171 European Americans and 772 African Americans were available.ResultsA total of 52 SNPs encompassing 7 loci showed suggestive evidence of association (p < 1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; p= 1.10 × 10−7), an association that was replicated (p = 0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; p= 2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (p < 5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (p = 3.97 × 10−8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (p= 0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively.ConclusionsOur results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women.

The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation.

This study characterized the kynurenine pathway (KP) in human obesity by evaluating circulating levels of kynurenines and the expression of KP enzymes in adipose tissue. Tryptophan and KP metabolite levels were measured in serum of individuals from the D.E.S.I.R. cohort (case-cohort study: 212 diabetic, 836 randomly sampled) and in women with obesity, diabetic or normoglycemic, from the ABOS cohort (n = 100). KP enzyme gene expressions were analyzed in omental and subcutaneous adipose tissue of women from the ABOS cohort, in human primary adipocytes and in monocyte-derived macrophages. In the D.E.S.I.R. cohort, kynurenine levels were positively associated with body mass index (BMI) (P = 4.68 × 10(-19) ) and with a higher HOMA2-IR insulin resistance index (P = 6.23 × 10(-4) ). The levels of kynurenine, kynurenic acid, and quinolinic acid were associated with higher BMI (P < 0.05). The expression of several KP enzyme genes (indoleamine 2,3-dioxygenase 1 [IDO1], kynureninase [KYNU], kynurenine 3-monooxygenase [KMO], and kynurenine aminotransferase III [CCBL2]) was increased in the omental adipose tissue of women with obesity compared to lean (P < 0.05), and their expression was induced by proinflammatory cytokines in human primary adipocytes (P < 0.05), except for KMO that is not expressed in these cells. The expressions of IDO1, KYNU, KMO, and CCBL2 were higher in proinflammatory than in anti-inflammatory macrophages (P < 0.05). In the context of obesity, the presence of macrophages in adipose tissue may contribute to diverting KP toward KMO activation.

Comprehensive assessment of expression of insulin signaling pathway components in subcutaneous adipose tissue of women with and without polycystic ovary syndrome

ObjectiveInsulin resistance is a common feature of polycystic ovary syndrome (PCOS). The insulin signaling pathway consists of two major pathways, the metabolic and the mitogenic cascades. The many components of these pathways have not been comprehensively analyzed for differential expression in insulin-responsive tissues in PCOS. The goal of this study was to determine whether the core elements of the insulin signal transduction cascade were differentially expressed in subcutaneous adipose tissue (SAT) between PCOS and controls. Materials/methodsQuantitative real-time PCR for 36 insulin signaling pathway genes was performed in subcutaneous adipose tissue from 22 white PCOS and 13 healthy controls. ResultsGenes in the insulin signaling pathway were not differentially expressed in subcutaneous adipose tissue between PCOS and controls (P > 0.05 for all). Components mainly of the mitogenic pathway were correlated with both androgens and metabolic phenotypes. Expression levels of five genes (MKNK1, HRAS, NRAS, KRAS, and GSK3A) were positively correlated with total testosterone level (ρ > 0, P < 0.05). Inverse correlation was found between expression of six genes (HRAS, MAP2K2, NRAS, MAPK3, GRB2, and SHC1) and metabolic traits (body mass index, fasting glucose, fasting insulin, and HOMA-IR) (ρ < 0, P < 0.05). ConclusionsDifferential expression of core insulin signaling pathway components in subcutaneous adipose tissue is not a major contributor to the pathogenesis of PCOS. Correlation between clinical phenotypes and expression of several genes in the mitogenic limb of the insulin signaling pathway suggests mitogenic signaling by insulin may regulate steroidogenesis and glucose homeostasis.

Serum vaspin levels and vaspin mRNA expression in subcutaneous adipose tissue in women with gestational diabetes mellitus

ObjectiveTo compare serum vaspin level and mRNA and protein levels of vaspin in adipose tissue in women with gestational diabetes mellitus (GDM) and normal glucose tolerance (NGR), along with the correlation between serum vaspin level with fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and birth-weight. Study designThirty-seven women with GDM and 36 with NGR were enrolled. Total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), FINS and vaspin levels were measured. The mRNA and protein levels were detected using RT-PCR and Western blot. Pearson correlation analysis (PCA) was performed to reveal the correlation between serum vaspin level and FINS, HOMA-IR. Spearman correlation analysis (SCA) was conducted to examine the association between serum vaspin level and birth-weight. ResultsHDL-C level in GDM was lower than NGR group (P<0.05), and there were no statistical differences in TC, TG, LDL-C, FPG, FINS and HOMA-IR between the two groups. Serum vaspin level, mRNA and protein expression levels of vaspin in GDM were higher than NGR group (P<0.05). Serum vaspin level was not significantly correlated with FINS and HOMA-IR, but had a positive correlation with birth-weight (P=0.023). ConclusionSerum vaspin level cannot serve as an independent predictor of IR. The increased serum vaspin level and increased vaspin mRNA and protein expression in adipose tissues in GDM women indicate that vaspin may be involved in the pathogenesis of GDM, but its exact mechanism needs further study.