Effect of a Customized Physical Activity Promotion Program on Visceral Fat and Glycemic Parameters in Individuals With Prediabetes: A Randomized Controlled Trial.

BACKGROUND: Physical activity of any amount results in substantial health benefits. However, public awareness of physical activity benefits in chronic diseases is inadequate in India. Prediabetes is a significant health issue on a global scale. Visceral fat (VF) is considered as an early predictor of prediabetes. Ethnicity and race have a substantial impact on VF. Hence, this study intended to evaluate the effect of a customized physical activity promotion program on VF and glycemic parameters in individuals with prediabetes. METHODS: In the current, parallel group randomized controlled trial, a total of 158 participants were recruited: 79 in intervention and 79 in control group. The study included the prediabetes individuals based on American Diabetes Association criteria. Participants from the intervention group received the customized physical activity promotion program for 24 weeks. The primary outcome measures of the study were VF level and glycemic parameters that included fasting blood sugar and glycosylated hemoglobin. Two-way mixed analysis of variance was used to study the mean difference of an outcome between 2 groups over time. RESULTS: The study found a statistically significant interaction between the intervention and times on VF level, F1,136 = 23.564, fasting blood sugar levels, F1,136 = 8.762, and glycosylated hemoglobin levels, F1,136 = 64.582 at the end of 24 weeks (P < .05). CONCLUSIONS: This study concluded that a customized physical activity promotion program was effective in reducing VF in individuals with prediabetes as compared with controls. It improved glycemic control by reducing fasting blood sugar and glycosylated hemoglobin levels.

Diet composition, nutrient substitutions and circulating fatty acids in relation to ectopic and visceral fat depots.

BACKGROUND & AIMS: Short-term randomized trials have demonstrated that replacing saturated fat (SFA) with polyunsaturated fat (PUFA) causes a reduction or prevention of liver fat accumulation, but population-based studies on diet and body fat distribution are limited. We investigated cross-sectional associations between diet, circulating fatty acids and liver fat, visceral adipose tissue (VAT), intermuscular adipose tissue (IMAT) and other fat depots using different energy-adjustment models. METHODS: Sex-stratified analyses of n = 9119 (for serum fatty acids) to 13 849 (for nutrients) participants in UK Biobank were conducted. Fat depots were assessed by MRI, circulating fatty acids by NMR spectroscopy and diet by repeated 24-h recalls. Liver fat, VAT and IMAT were primary outcomes; total adipose tissue (TAT) and abdominal subcutaneous adipose tissue (ASAT) were secondary outcomes. Three a priori defined models were constructed: the all-components model, standard model and leave-one-out model (main model including specified nutrient substitutions). Imiomics (MRI-derived) was used to confirm and visualize associations. RESULTS: In women, substituting carbohydrates and free sugars with saturated fat (SFA) was positively associated with liver fat (ß (95% CI) = 0.19 (0.02, 0.36) and ß (95% CI) = 0.20 (0.05-0.35), respectively) and IMAT (ß (95% CI) = 0.07 (0.00, 0.14) and ß (95% CI) = 0.08 (0.02, 0.13), respectively), whereas substituting animal fat with plant fat was inversely associated with IMAT, ASAT and TAT. In the all-components and standard models, SFA and animal fat were positively associated with liver fat, IMAT and VAT whereas plant fat was inversely associated with IMAT in women. Few associations were observed in men. Circulating polyunsaturated fatty acids (PUFA) were inversely associated with liver fat, IMAT and VAT in both men and women, whereas SFA and monounsaturated fatty acids were positively associated. CONCLUSIONS: Type of dietary fat may be an important determinant of ectopic fat in humans consuming their habitual diet. Plant fat and PUFA should be preferred over animal fat and SFA. This is corroborated by circulating fatty acids and overall consistent through different energy adjustment models. TWITTER SUMMARY: In UK Biobank, intake of saturated- and animal fat were positively whereas biomarkers of polyunsaturated fat were inversely associated with liver-, visceral- and intermuscular fat. Type of dietary fat may be a determinant of ectopic fat, a risk factor for cardiometabolic disease.

Visceral fat correlates with insulin secretion and sensitivity independent of BMI and subcutaneous fat in Chinese with type 2 diabetes.

Aim: Clinical heterogeneity exists in overall obesity and abdominal obesity in terms of insulin secretion and sensitivity. Further, the impact of visceral fat (VF) on the first- and second-phase insulin secretion (FPIS and SPIS) is controversial. We aim to investigate insulin secretion and sensitivity in Chinese patients with T2DM according to different BMI and VF levels. Methods: This study enrolled 300 participants. A dual bioelectrical impedance analyzer was used to assess the visceral and subcutaneous fat area (VFA and SFA). VF levels were categorized as normal or high, with the cutoff value of 100 cm2. FPIS and SPIS were evaluated by arginine stimulation test and standardized steamed bread meal tolerance test, respectively. ß-cell function (HOMA2-ß), insulin resistance (HOMA2-IR), and Gutt's insulin sensitivity index (Gutt-ISI) were also calculated. Spearman's correlation analysis and multivariate linear regression analysis were adopted for statistical analysis. Results: Participants were categorized into four groups: normal weight-normal VF, normal weight-high VF, overweight/obese-normal VF and overweight/obese-high VF. Multivariate linear regression showed that both VFA and SFA were correlated with FPIS, HOMA2-IR and Gutt-ISI after controlling for gender and diabetes duration. After further adjustment for BMI and VFA, some associations of SFA with insulin secretion and sensitivity disappeared. After adjustment for gender, diabetes duration, BMI and SFA, VFA was positively correlated with FPIS, SPIS and HOMA2-IR. Subjects with overweight/obese-high VF were more likely to have higher FPIS, HOMA2-IR and lower Gutt-ISI (all p < 0.05). Conclusion: VF affects both FPIS and SPIS, and worsens insulin sensitivity independent of BMI and subcutaneous fat in Chinese patients with T2DM. Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2200062884.

Heterogeneous miRNA-mRNA Regulatory Networks of Visceral and Subcutaneous Adipose Tissue in the Relationship Between Obesity and Renal Clear Cell Carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urologic cancer. Associations of both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with ccRCC have been reported, and underlying mechanisms of VAT perhaps distinguished from SAT, considering their different structures and functions. We performed this study to disclose different miRNA-mRNA networks of obesity-related ccRCC in VAT and SAT using datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA); and find out different RNAs correlated with the prognosis of ccRCC in VAT and SAT. Methods: We screened out different expressed (DE) mRNAs and miRNAs of obesity, in both VAT and SAT from GEO datasets, and constructed miRNA-mRNA networks of obesity-related ccRCC. To evaluate the sensitivity and specificity of RNAs in networks of obesity-related ccRCC in both VAT and SAT, Receiver Operating Characteristic (ROC) analyses were conducted using TCGA datasets. Spearman correlation analyses were then performed to find out RNA pairs with inverse correlations. We also performed Cox regression analyses to estimate the association of all DE RNAs of obesity with the overall survival. Results: 136 and 185 DE mRNAs of obesity in VAT and SAT were found out. Combined with selected DE miRNAs, miRNA-mRNA networks of obesity-related ccRCC were constructed. By performing ROC analyses, RNAs with same trend as shown in networks and statistically significant ORs were selected to be paired. Three pairs were finally remained in Spearman correlation analyses, including hsa-miR-182&ATP2B2, hsa-miR-532&CDH2 in VAT, and hsa-miR-425&TFAP2B in SAT. Multivariable Cox regression analyses showed that several RNAs with statistically significant adjusted HRs remained consistent trends as shown in DE analyses of obesity. Risk score analyses using selected RNAs showed that the overall survival time of patients in the low-risk group was significantly longer than that in the high-risk group regardless of risk score models. Conclusions: We found out different miRNA-mRNA regulatory networks of obesity-related ccRCC for both VAT and SAT; and several DE RNAs of obesity-related ccRCC were found to remain consistent performance in terms of ccRCC prognosis. Our findings could provide valuable evidence on the targeted therapy of obesity-related ccRCC.

Effect of Continuous Feeding of Ayu-Narezushi on Lipid Metabolism in a Mouse Model of Metabolic Syndrome.

Ayu-narezushi, a traditional Japanese fermented food, comprises abundant levels of lactic acid bacteria (LAB) and free amino acids. This study aimed to examine the potential beneficial effects of ayu-narezushi and investigated whether ayu-narezushi led to improvements in the Tsumura Suzuki obese diabetes (TSOD) mice model of spontaneous metabolic syndrome because useful LAB are known as probiotics that regulate intestinal function. In the present study, the increased body weight of the TSOD mice was attenuated in those fed the ayu-narezushi-comprised chow (ayu-narezushi group) compared with those fed the normal rodent chow (control group). Serum triglyceride and cholesterol levels were significantly lower in the Ayu-narezushi group than in the control group at 24 weeks of age. Furthermore, hepatic mRNA levels of carnitine-palmitoyl transferase 1 and acyl-CoA oxidase, which related to fatty acid oxidation, were significantly increased in the ayu-narezushi group than in the control group at 24 weeks of age. In conclusion, these results suggested that continuous feeding with ayu-narezushi improved obesity and dyslipidemia in the TSOD mice and that the activation of fatty acid oxidation in the liver might contribute to these improvements.

White adipose tissue-infiltrated CD11b+ myeloid cells are a source of S100A4, a new potential marker of hepatic damage.

CONTEXT: The endocrine and immunological properties of subcutaneous vs visceral adipose tissue (sWAT and vWAT, respectively) have turned a milestone in the study of metabolic diseases. The cytokine S100A4 is increased in obesity and has a role in adipose tissue dysfunction. However, the cellular source and its potential role in hepatic damage in obesity has not been elucidated. OBJECTIVE: We aim to study the regulation of S100A4 in immune cells present in sWAT and vWAT, as well as its potential role as a circulating marker of hepatic inflammation and steatosis. DESIGN: A cohort of 60 patients with obesity and distinct metabolic status was analyzed. CD11b+ myeloid cells and T cells were isolated from sWAT and vWAT by magnetic-activating cell sorting, and RNA was obtained. S100A4 gene expression was measured, and correlation analysis with clinical data was performed. Liver biopsies were obtained from 20 patients, and S100A4 circulating levels were measured to check the link with hepatic inflammation and steatosis. RESULTS: S100A4 gene expression was strongly upregulated in sWAT- vs vWAT-infiltrated CD11b+ cells, but this modulation was not observed in T cells. S100A4 mRNA levels from sWAT (and not from vWAT) CD11b+ cells positively correlated with glycemia, triglycerides, TNF-α gene expression and proliferation markers. Finally, circulating S100A4 directly correlated with liver steatosis and hepatic inflammatory markers. CONCLUSION: Our data suggest that sWAT-infiltrated CD11b+ cells could be a major source of S100A4 in obesity. Moreover, our correlations identify circulating S100A4 as a potential novel biomarker of hepatic damage and steatosis.

Weight loss normalizes enhanced expression of the oncogene survivin in visceral adipose tissue and blood leukocytes from individuals with obesity.

BACKGROUND/OBJECTIVES: Survivin is an oncogene associated with a decrease in apoptosis, an increase in tumor growth, and poor clinical outcome of diverse malignancies. A correlation between obesity, cancer, and survivin is reported in the literature. To date, the impact of weight loss on change in survivin levels is understudied. This study was aimed at: (1) comparing survivin levels in adipose tissue (AT) from lean and obese animal models and evaluating changes after weight loss induced by energy restriction and/or exercise; (2) comparing survivin levels in normal weighted and obese humans and evaluating changes in survivin levels after weight loss induced by a very-low-calorie ketogenic diet (VLCKD) or bariatric surgery in AT and/or blood leukocytes (PBL/PBMCs). SUBJECTS/METHODS: Survivin expression was evaluated in subcutaneous (SAT) and visceral (VAT) AT derived from animal models of monogenic (Zucker rats) and diet-induced obesity (Sprague Dawley rats and C57BL/6J mice) and after a 4-week weight-loss protocol of energy restriction and/or exercise. Plasma was used to measure the inflammatory status. Survivin expression was also evaluated in PBMCs from patients with obesity and compared with normal weight, in PBLs after VLCKD, and in SAT and/or PBLs after bariatric surgery. RESULTS: Survivin expression was specifically higher in VAT from obese that lean animals, without differences in SAT. It decreased after weight loss induced by energy restriction and correlated with adiposity and inflammatory markers. In humans, the correlation between being obese and higher levels of survivin was confirmed. In obese subjects, survivin levels were reduced following weight loss after either VLCKD or bariatric surgery. Particularly, a decrease in PBMCs expression (not in SAT one) was found after surgery. CONCLUSIONS: Weight loss is effective in decreasing survivin levels. Also, PBL/PBMC should be regarded as appropriate mirror of survivin levels in VAT for the identification of an obesity-related protumoral microenvironment.

Resolving the omega-3 methyl resonance with long echo time magnetic resonance spectroscopy in mouse adipose tissue at 9.4 T.

Tissue omega-3 (ω-3) content is biologically important to disease; however, its quantification with magnetic resonance spectroscopy in vivo is challenging due to its low concentration. In addition, the ω-3 methyl resonance (≈ 0.98 ppm) overlaps that of the non-ω-3 (≈ 0.90 ppm), even at 9.4 T. We demonstrate that a Point-RESolved Spectroscopy (PRESS) sequence with an echo time (TE) of 109 ms resolves the ω-3 and non-ω-3 methyl peaks at 9.4 T. Sequence efficacy was verified on five oils with differing ω-3 fat content; the ω-3 content obtained correlated with that measured using 16.5 T NMR (R2 = 0.97). The PRESS sequence was also applied to measure ω-3 content in visceral adipose tissue of three different groups (all n = 3) of mice, each of which were fed a different 20% w/w fat diet. The fat portion of the diet consisted of low (1.4%), medium (9.0%) or high (16.4%) ω-3 fat. The sequence was also applied to a control mouse fed a standard chow diet (5.6% w/w fat, which was 5.9% ω-3). Gas chromatography (GC) analysis of excised tissue was performed for each mouse. The ω-3 fat content obtained with the PRESS sequence correlated with the GC measures (R2 = 0.96). Apparent T2 times of methyl protons were assessed by obtaining spectra from the oils and another group of four mice (fed the high ω-3 diet) with TE values of 109 and 399 ms. Peak areas were fit to a mono-exponentially decaying function and the apparent T2 values of the ω-3 and non-ω-3 methyl protons were 906 ± 148 and 398 ± 78 ms, respectively, in the oils. In mice, the values were 410 ± 68 and 283 ± 57 ms for ω-3 and non-ω-3 fats, respectively.

Visceral adiposity index is associated with silent brain infarct in a healthy population.

Visceral adiposity index (VAI) has been associated with various cardio-metabolic diseases; however, there is limited information about its association with cerebrovascular diseases. In this study, we evaluated the relationship between VAI and silent brain infarct (SBI). We evaluated a consecutive series of healthy volunteers over the age of 40 between January 2006 and December 2013. SBI was defined as an asymptomatic, well-defined lesion with a diameter ≥ 3 mm with the same signal characteristics as the cerebrospinal fluid. VAI was calculated using sex-specific equations as described in previous studies. A total of 2596 subjects were evaluated, and SBI was found in 218 (8%) participants. In multivariable analysis, VAI (adjusted odds ratio [aOR] = 1.30; 95% confidence interval [CI] 1.03-1.66; P = 0.030) remained a significant predictor of SBI after adjustment for confounders. The close relationship between VAI and SBI was prominent only in females (aOR = 1.44; 95% CI 1.00-2.07; P = 0.048). In the evaluation between VAI and the burden of SBI, VAI showed a positive dose-response relationship with the number of SBI lesions (P for trend = 0.037). High VAI was associated with a higher prevalence and burden of SBI in a neurologically healthy population.

Ovariectomy modifies lipid metabolism of retroperitoneal white fat in rats: a proteomic approach.

Menopause is often accompanied by visceral obesity. With the aim of exploring the consequences of ovarian failure on visceral fat, we evaluated the effects of ovariectomy and estrogen replacement on the proteome/phosphoproteome and on the fatty acid profile of the retroperitoneal adipose depot (RAT) of rats. Eighteen 3-mo-old female Wistar rats were either ovariectomized or sham operated and fed with standard chow for 3 mo. A subgroup of ovariectomized rats received estradiol replacement. RAT samples were analyzed with data-independent acquisitions LC-MS/MS, and pathway analysis was performed with the differentially expressed/phosphorylated proteins. RAT lipid profile was analyzed by gas chromatography. Ovariectomy induced high adiposity and insulin resistance and promoted alterations in protein expression and phosphorylation. Pathway analysis showed that five pathways were significantly affected by ovariectomy, namely, metabolism of lipids (including fatty acid metabolism and mitochondrial fatty acid ß-oxidation), fatty acyl-CoA biosynthesis, innate immune system (including neutrophil degranulation), metabolism of vitamins and cofactors, and integration of energy metabolism (including ChREBP activates metabolic gene expression). Lipid profile analysis showed increased palmitic and palmitoleic acid content. The analysis of the data indicated that ovariectomy favored lipogenesis whereas it impaired fatty acid oxidation and induced a proinflammatory state in the visceral adipose tissue. These effects are consistent with the findings of high adiposity, hyperleptinemia, and impaired insulin sensitivity. The observed alterations were partially attenuated by estradiol replacement. The data point to a role of disrupted lipid metabolism in adipose tissue in the genesis of obesity after menopause.

Distinct abdominal and gluteal adipose tissue transcriptome signatures are altered by exercise training in African women with obesity.

The differential associations of adipose depots with metabolic risk during obesity have been proposed to be controlled by environmental and genetic factors. We evaluated the regional differences in transcriptome signatures between abdominal (aSAT) and gluteal subcutaneous adipose tissue (gSAT) in obese black South African women and tested the hypothesis that 12-week exercise training alters gene expression patterns in a depot-specific manner. Twelve young women performed 12-weeks of supervised aerobic and resistance training. Pre- and post-intervention measurements included peak oxygen consumption (VO2peak), whole-body composition and unbiased gene expression analysis of SAT depots. VO2peak increased, body weight decreased, and body fat distribution improved with exercise training (p < 0.05). The expression of 15 genes, mainly associated with embryonic development, differed between SAT depots at baseline, whereas 318 genes were differentially expressed post-training (p < 0.05). Four developmental genes were differentially expressed between these depots at both time points (HOXA5, DMRT2, DMRT3 and CSN1S1). Exercise training induced changes in the expression of genes associated with immune and inflammatory responses, and lipid metabolism in gSAT, and muscle-associated processes in aSAT. This study showed differences in developmental processes regulating SAT distribution and expandability of distinct depots, and depot-specific adaptation to exercise training in black South African women with obesity.

Genetic architecture underlying changes in carotenoid accumulation during the evolution of the blind Mexican cavefish, Astyanax mexicanus.

Carotenoids are lipid-soluble yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and, therefore, limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed. Astyanax mexicanus is a species of fish with multiple river-adapted (surface) and cave-adapted populations (i.e., Tinaja, Pachón, Molino). Cavefish exhibit regressive features, such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here, we show that, unlike surface fish, Tinaja and Pachón cavefish accumulate carotenoids in the visceral adipose tissue. Carotenoid accumulation is not observed in Molino cavefish, indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci mapping and RNA sequencing to investigate genetic changes associated with carotenoid accumulation. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into unpigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishes A. mexicanus as a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.

Minimizing Visceral Fat Delocalization on Tissue Sections with Porous Aluminum Oxide Slides for Imaging Mass Spectrometry.

A high correlation of bioanalytes with their corresponding histologies is the landmark feature of matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS). Lipids are one of the most studied classes of biomolecules, and monitoring lipid distribution and abundance in tissue samples can lead to major inputs in the understanding of disease. Lipid delocalization and ion suppression are two major effects that can lead to misinterpretation of the IMS results to an unaware analyst. We and others have observed that tissue specimens containing high amounts of visceral fat are challenging to analyze because of fat delocalization on and off section leading to significant triacylglyceride and phospholipid delocalization and major ion suppression effects. In this work, we introduce a novel and easy to produce reusable porous aluminum oxide sample slide that minimizes visceral fat delocalization after thaw-mounting of tissue sections. Using fatty mouse kidneys and other tissues, we demonstrate its efficacy in minimizing delocalization of triacylglycerides, the primary constituents of fat, and the resulting beneficial effects on phospholipid MALDI IMS.

Targeted lipidomics and transcriptomics profiling reveal the heterogeneity of visceral and subcutaneous white adipose tissue.

AIMS: The depot-specific differences in lipidome of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) reflect heterogeneity of white adipose tissue (WAT), which plays a central role in its distinct response to outside stimuli. However, the detailed lipidome of depot-specific WAT is largely unknown, especially the minor constitutes including phospholipid and sphingolipid. MATERIALS AND METHODS: To investigate this field, we applied a high-coverage targeted lipidomics approach of VAT and SAT in male C57BL/6J mice to compare the basal level of their lipid profiles. Applying microarray and quantitative real-time polymerase chain reaction, we analyzed the transcriptome of twodepot-specific WAT and verified the differences in individual genes. KEY FINDINGS: In total, 342 lipid species from 19 lipid classes were identified. Our results showed the composition of TAG and FFA were different in length of chain and saturation. Interestingly, low abundance phospholipid, sphingolipid and cardiolipin were significantly higher in SAT. Lipid correlation network analysis vindicated that TAG and phospholipid formed distinct subnet and had more connections with other lipid species. Enriched ontology analysis of gene screened from LIPID MAPS and microarray suggested the differences were mainly involved in lipid metabolism, insulin resistance and inflammatory response. SIGNIFICANCE: Our comprehensive lipidomics and transcriptomics analyses revealed differences in lipid composition and lipid metabolism of two depot-specific WAT, which would offer new insights into the investigation of heterogeneity of visceral and subcutaneous white adipose tissue.

FAHFA footprint in the visceral fat of mice across their lifespan.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with anti-inflammatory and anti-diabetic effects, having the potential to treat type 2 diabetes (T2D). In view of the important regulatory and therapeutic actions of FAHFAs on age-related diseases such as T2D, we hypothesized that they may also play crucial roles in the growth, development, and aging process. Here, we investigated the FAHFA footprint in the visceral adipose tissue (VAT) of mice across lifespan to attain potential clues for understanding the roles of FAHFAs in growth, development, and aging using chemical isotope labeling assisted liquid chromatography-mass spectrometry. VAT samples were harvested from 80 C57BL/6J male mice of nine different ages (1, 2, 3, 6, 9, 12, 15, 18, and 24 months). The results showed that a total of 51 FAHFA families, including 301 regioisomers, were detected in the VAT of mice of all ages, and the number of FAHFAs (both family and regioisomer) in VAT increased with age, from 35 families (186 ± 0 regioisomers) at 1-month-old mice to 46 families (278 ± 6 regioisomers) in 18-month-old mice. Furthermore, the content of 12 FAHFA families per 100 mg of VAT of mice was highly correlated with age, and was usually low in the middle-age (3-15 months). However, because the VAT mass was 4-5 fold higher in middle-aged mice compared to younger or older mice, the total amount of most of the FAHFA regioisomers in VAT was increased in middle-aged mice. To the best of our knowledge, this is the first study to show that the number of regioisomers from 51 FAHFA families and abundance of 15 FAHFA families are strongly dependent on age, which would be helpful for understanding the mechanisms underlying the effects of FAHFAs on growth, development, and aging.

Relationships between visceral/subcutaneous adipose tissue FABP4 expression and coronary atherosclerosis in patients with metabolic syndrome.

BACKGROUND: Cytoplasmic fatty acid-binding proteins facilitate the transport of lipids to specific compartments in cells. Fatty acid-binding protein 4 (FABP4), also known as aP2 or A-FABP, plays a key role in the development of atherosclerosis, insulin resistance, obesity, and metabolic syndrome (MS). The FABP4 polymorphisms are associated with protein expression changes in vitro and metabolic and vascular alterations in vivo. The aim of this study was to investigate the association between FABP4 messenger ribonucleic acid (mRNA) expression levels in epicardial (EAT), pericardial (PAT), and subcutaneous adipose tissues (SAT), and the extent of coronary atherosclerosis in coronary artery disease (CAD) patients with MS. Furthermore, the relationship between the extent of coronary atherosclerosis and epicardial adipose tissue volume (EATV) and FABP4 gene variations was evaluated. PATIENTS AND METHODS: A total of 37 patients undergoing coronary artery bypass grafting because of CAD (MS CAD group) and 23 non-MS patients undergoing heart valve surgery (control group) were included. Coronary angiography was performed for all patients and the extent of coronary atherosclerosis was assessed using the Sullivan's scoring system. The mRNA expression levels of FABP4 gene in EAT, PAT, and SAT, and FABP4 polymorphisms were analyzed using the quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: An increased FABP4 expression was observed in EAT and PAT of MS CAD group compared to controls. In the MS CAD group, FABP4 mRNA expression levels in EAT was 2.8-fold higher compared to PAT. The expression of FABP4 in EAT was positively correlated with the extent of atherosclerosis and EATV in MS CAD group (r = 0.588, P= 0.001, r = 0.174, P = 0.001, respectively). There were no correlations between PAT and SAT versus the extent of atherosclerosis and EATV. The FABP4 EAT mRNA expression levels were found to significantly increase in mutant allele carriers of rs1054135, whereas they significantly decreased in mutant allele carriers of rs77878271 (T-87C) in MS CAD group (P < 0.05). The extent of atherosclerosis was also found to be significantly associated with rs1054135 (P < 0.05). A cut-off point of 57.5 cm3 EATV was used indicating the presence of CAD with a significant area under the curve of 0.783%, 98% sensitivity, and 100% specificity (95% CI 0.620-0.880; P < 0.05). CONCLUSIONS: Our study results suggest that FABP4 expression in EAT is strongly associated with the extent of atherosclerosis and EATV in MS CAD patients.

Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity.

BACKGROUND: There is solid evidence that obesity induces the acceleration of liver epigenetic aging. However, unlike easily accessible blood or subcutaneous adipose tissue, little is known about the impact of obesity on epigenetic aging of metabolically active visceral adipose tissue (VAT). Herein, we aimed to test whether obesity accelerates VAT epigenetic aging in subjects with severe obesity. RESULTS: A significant and positive correlation between chronological age and epigenetic age, estimated with a reduced version of the Horvath's epigenetic clock, was found in both blood (r = 0.78, p = 9.4 × 10-12) and VAT (r = 0.80, p = 1.1 × 10-12). Epigenetic age acceleration, defined as the residual resulting from regressing epigenetic age on chronological age, was significantly correlated with body mass index (BMI) in VAT (r = 0.29, p = 0.037). Multivariate linear regression analysis showed that, after adjusting for chronological age, sex and metabolic syndrome status, BMI remained significantly associated with epigenetic age acceleration in VAT (beta = 0.15, p = 0.035), equivalent to 2.3 years for each 10 BMI units. Binomial logistic regression showed that BMI-adjusted epigenetic age acceleration in VAT was significantly associated with a higher loss of excess body weight following biliopancreatic diversion with duodenal switch surgery (odds ratio = 1.21; 95% CI = 1.04-1.48; p = 0.03). CONCLUSIONS: Epigenetic age acceleration increases with BMI in VAT, but not in blood, as previously reported in liver. These results suggest that obesity is associated with epigenetic age acceleration of metabolically active tissues. Further studies that deepen the physiological relevance of VAT epigenetic aging will help to better understand the onset of metabolic syndrome and weight loss dynamics following bariatric surgery.

A New LC-MS/MS Method for Simultaneous and Quantitative Detection of Bisphenol-A and Steroids in Target Tissues: A Power Tool to Characterize the Interference of Bisphenol-A Exposure on Steroid Levels.

Bisphenol A (BPA), an endocrine disruptor, may affect in situ steroidogenesis and alter steroids levels. The present work proposes a liquid chromatography tandem mass spectrometry method to simultaneously quantify BPA, 17ß-Estradiol and testosterone in two target tissues: testis and visceral fat mass. Analytes were isolated and lipophilic impurities removed by two serial steps: liquid-liquid and solid phase extraction. All compounds were separated in a single gradient run by Kinetex F5 column and detected via multiple reaction monitoring using a triple quadrupole with a TurboIon electrospray source in both negative and positive modes. The method is selective and very sensitive. In the investigated concentration range, the linearity of the detector response is verified in both tissues. The use of specific SPE cartridges for affinity chromatography purification allows obtaining high percentages of process efficiency (68.0-83.3% for testicular tissue; 63.7-70.7% for visceral fat mass). Good repeatability and reproducibility was observed. The validated method can be efficiently applied for direct biological monitoring in testis and visceral fat mass from mice exposed to BPA. The quantification of compounds in a single assay could be achieved without a loss of sensitivity.

Visceral adipose tissue alteration of PI3KR1 expression is associated with gestational diabetes but not promoter DNA methylation.

Obesity and diabetes are at an epidemic rate, as well as growing incidences of gestational diabetes mellitus (GDM) which causes pregnancy risks, and harm in both maternal and child health. It remains unclear which molecular mechanisms are driving the functional differences between visceral and subcutaneous fat and how these types directly affect an individual's health outcome. Paired abdominal subcutaneous and omental visceral adipose tissue were collected from women with GDM (n = 20) and with normal glucose tolerance (NGT, n = 22) during planned caesarian section. Both groups had similar maternal age (average 32.5 years) and BMI at delivery (average 33.3 kg/m2). Adipose tissue mRNA expression analyses of insulin signalling genes: PI3KCA, PI3KR1, IRS1 and IRS2 showed significantly decreased PI3KR1 expression (-23%) in visceral fat in GDM with no association to promoter DNA methylation. Reduced visceral fat PI3KR1 expression appears to be a pathogenic factor in GDM but not through altered promoter methylation.

Metabolomics: a search for biomarkers of visceral fat and liver fat content.

INTODUCTION: Excess visceral and liver fat are known risk factors for cardiometabolic disorders. Metabolomics might allow for easier quantification of these ectopic fat depots, instead of using invasive and costly tools such as MRI or approximations such as waist circumference. OBJECTIVE: We explored the potential use of plasma metabolites as biomarkers of visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC). METHODS: We performed a cross-sectional analysis of a subset of the Netherlands Epidemiology of Obesity study. Plasma metabolite profiles were determined using the Biocrates AbsoluteIDQ p150 kit in 176 individuals with normal fasting plasma glucose. VAT was assessed with magnetic resonance imaging and HTGC with proton-MR spectroscopy. We used linear regression to investigate the associations of 190 metabolite variables with VAT and HTGC. RESULTS: After adjustment for age, sex, total body fat, currently used approximations of visceral and liver fat, and multiple testing, three metabolite ratios were associated with VAT. The strongest association was the lysophosphatidylcholines to total phosphatidylcholines (PCs) ratio [- 14.1 (95% CI - 21.7; - 6.6) cm2 VAT per SD of metabolite concentration]. Four individual metabolites were associated with HTGC, especially the diacyl PCs of which C32:1 was the strongest at a 1.31 (95% CI 1.14; 1.51) fold increased HTGC per SD of metabolite concentration. CONCLUSION: Metabolomics may be a useful tool to identify biomarkers of visceral fat and liver fat content that have added diagnostic value over current approximations. Replication studies are required to validate the diagnostic value of these metabolites.