Depot-Specific Adipose Tissue Metabolite Profiles and Corresponding Changes Following Aerobic Exercise

Objectives: Total, visceral, and abdominal subcutaneous adipose tissue (AT) depots have distinct associations with cardiometabolic health; however, the metabolite profiles that characterize each AT depot and its reduction following exercise are poorly understood. Our objectives were to (1) assess the independent associations between identified metabolites and total, visceral and abdominal subcutaneous AT; and (2) examine whether changes in metabolite concentrations and AT mass following aerobic exercise are associated.Methods: A secondary analysis was performed in 103 middle-aged abdominally obese men and women {[mean (SD)], 52.4 (8.0) years} randomized into one of four groups varying in exercise amount and intensity for 6 months duration: high amount high intensity, high amount low intensity, low amount low intensity, and control. One hundred and forty seven metabolites were profiled by liquid chromatography-tandem mass spectrometry. AT mass was measured by magnetic resonance imaging (MRI).Results: Individual metabolite associations with AT depots confirmed several established cross-sectional relationships between the obesity phenotype and metabolic pathways. Collapsed across exercise groups, reduction in visceral AT predicted increases in pyroglutamic acid (B = −0.41) and TCA cycle intermediates [succinic (B = −0.41) and fumaric acid (B = −0.20)], independent of change in total AT. Changes in UDP-GlcNAc (B = 0.43), pyroglutamic acid (B = −0.35), histidine (B = 0.20), citric acid/isocitric acid (B = −0.20), and creatine (B = 0.27) were significantly associated with changes in total AT (false discovery rate = 0.1).Conclusions: Our findings point to potential biomarkers of depot-specific AT reduction that may play a direct role in mediating cardiometabolic improvements

Diabetes, Abdominal Adiposity, and Atherogenic Dyslipoproteinemia in Women Compared With Men

OBJECTIVE—To understand why atherogenic risk differs more between diabetic and nondiabetic women than between diabetic and nondiabetic men

Diabetes, Abdominal Adiposity, and Atherogenic Dyslipoproteinemia in Women Compared With Men

OBJECTIVE—To understand why atherogenic risk differs more between diabetic and nondiabetic women than between diabetic and nondiabetic men

Contribution of abdominal adiposity to age-related differences in insulin sensitivity and plasma lipids in healthy nonobese women

WSTĘP. Autorzy sprawdzili słuszność hipotezy zakładającej, że związany z wiekiem przyrost tkanki tłuszczowej trzewnej odpowiada częściowo za ujemny wpływ na insulinowrażliwość i profil lipidowy u kobiet bez otyłości. MATERIAŁ I METODY. Bezpośrednio oceniono: powierzchnię podskórnej i trzewnej tkanki tłuszczowej (tomografia komputerowa), zużycie glukozy (badanie metodą hiperinsulinowej/euglikemicznej klamry metabolicznej), elementy składowe organizmu (metoda absorpcjometrii promieniami X dwoistej energii), profil lipidowy oraz maksymalne zużycie tlenu (VO2max) u 178 kobiet bez otyłości, zakwalifikowanych do odpowiednich grup wiekowych: grupa 1 - 28 &plusmn; 4 lata (n = 88); grupa 2 - 46 &plusmn; 2 lata (n = 38); grupa 3 - 53 &plusmn; 2 lata (n = 31); grupa 4 - 67 &plusmn; 6 lat (n = 21). WYNIKI. Powierzchnia trzewnej tkanki tłuszczowej zwiększa się wraz z wiekiem (2,36 cm2 rocznie, p < 0,0001). Zanotowano związany z wiekiem wzrost stężenia cholesterolu całkowitego (p < 0,0003), triglicerydów (p < 0,0009), cholesterolu frakcji LDL (p < 0,027) i stosunku stężenia cholesterolu całkowitego do cholesterolu frakcji HDL (p < 0,042). Obserwowane różnice w insulinowrażliwości także wiązały się z wiekiem, jednakże w tym przypadku zależność była odmienna. Insulinowrażliwość, wyrażona jako całkowita lub przeliczona na kilogram beztłuszczowej masy ciała, była najniższa w grupie 4, ale nie różniła się istotnie między grupami 1, 2 i 3. Po analizie statystycznej, uwzględniającej powierzchnię tkanki tłuszczowej trzewnej, niższa insulinowrażliwość utrzymywała się, jednocześnie, relatywnie zmniejszyła się różnica w porównaniu z pozostałymi grupami. Wpływ zawartości trzewnej tkanki tłuszczowej na związane z wiekiem zmiany profilu lipidowego był silniejszy. Różnice w powierzchni trzewnej i głębokiej podskórnej tkanki tłuszczowej znosiły wpływ wieku na stężenie cholesterolu całkowitego, triglicerydów i cholesterolu frakcji LDL. Nie obserwowano natomiast wpływu wartości VO2max lub aktywnego wypoczynku na zależne od wieku zmiany w insulinowrażliwości bądź profilu lipidowym. WNIOSKI. 1) Wraz z wiekiem zwiększa się powierzchnia trzewnej tkanki tłuszczowej, podczas gdy zmniejszenie insulinowrażliwości obserwuje się tylko u kobiet starszych; 2) Związane z wiekiem różnice w trzewnej tkance tłuszczowej tylko w niewielkim stopniu odpowiadają za spadek insulinowrażliwości u kobiet bez otyłości; 3) Niepożądane zmiany profilu lipidowego w dużym stopniu wiążą się z zależnym od wieku przyrostem trzewnej tkanki tłuszczowej.INTRODUCTION. We examined the hypothesis that an age-related increase in the compartments of visceral fat would account, in part, for the deleterious changes in insulin sensitivity and blood lipid profile in nonobese women. MATERIAL AND METHODS. We directly assessed visceral and subcutaneous abdominal adipose tissue areas (computed tomography), glucose disposal (hyperinsulinemic-euglycemic clamp), body composition (dual energy X-ray absorptiometry), blood-lipid profile, and aerobic fitness (VO2max) in 178 nonobese women categorized into four age groups: group 1, 28 &plusmn; 4 years, n = 88; group 2, 46 &plusmn; 2 years, n = 38; group 3, 53 &plusmn; 2 years, n = 31; and group 4, 67 &plusmn; 6 years, n = 21. RESULTS. Visceral abdominal adipose tissue area increased with age (2.36 cm2 per year, P < 0.0001). We noted an age-related increase in total cholesterol (P < 0.0003), triglycerides (P < 0.0009), LDL cholesterol (P < 0.027), and the ratio of total cholesterol to HDL cholesterol (P < 0.042). However, agerelated changes in insulin sensitivity exhibited a different age-related pattern. That is, insulin sensitivity, expressed on an absolute basis or indexed per kilogram of fat-free mass, was lowest in group 4 but was not significantly different among groups 1, 2, and 3. After statistical control for visceral fat, lower insulin sensitivity persisted in group 4, although differences were diminished relative to other groups. However, the effect of visceral fat on agerelated changes in the blood-lipid profile was stronger. That is, differences in visceral and deep subcutaneous adipose tissue area abolished age-related differences in total cholesterol, triglycerides, and LDL cholesterol. No independent effects of VO2max or leisure-time physical activity on age-related changes in insulin sensitivity or on the blood-lipid profile were noted. CONCLUSIONS. We conclude that 1) visceral fat shows an increase with advancing age, whereas a decrease in insulin sensitivity was noted only in older women; 2) age-related differences in visceral fat explain only a modest part of the decline in insulin sensitivity in nonobese women; and 3) unfavorable changes in plasma lipids were strongly associated with the age-related increase in visceral abdominal adipose tissue

Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers

Background There is considerable evidence for the importance of the DNA methylome in metabolic health, for example, a robust methylation signature has been associated with body mass index (BMI). However, visceral fat (VF) mass accumulation is a greater risk factor for metabolic disease than BMI alone. In this study, we dissect the subcutaneous adipose tissue (SAT) methylome signature relevant to metabolic health by focusing on VF as the major risk factor of metabolic disease. We integrate results with genetic, blood methylation, SAT gene expression, blood metabolomic, dietary intake and metabolic phenotype data to assess and quantify genetic and environmental drivers of the identified signals, as well as their potential functional roles. Methods Epigenome-wide association analyses were carried out to determine visceral fat mass-associated differentially methylated positions (VF-DMPs) in SAT samples from 538 TwinsUK participants. Validation and replication were performed in 333 individuals from 3 independent cohorts. To assess functional impacts of the VF-DMPs, the association between VF and gene expression was determined at the genes annotated to the VF-DMPs and an association analysis was carried out to determine whether methylation at the VF-DMPs is associated with gene expression. Further epigenetic analyses were carried out to compare methylation levels at the VF-DMPs as the response variables and a range of different metabolic health phenotypes including android:gynoid fat ratio (AGR), lipids, blood metabolomic profiles, insulin resistance, T2D and dietary intake variables. The results from all analyses were integrated to identify signals that exhibit altered SAT function and have strong relevance to metabolic health. Results We identified 1181 CpG positions in 788 genes to be differentially methylated with VF (VF-DMPs) with significant enrichment in the insulin signalling pathway. Follow-up cross-omic analysis of VF-DMPs integrating genetics, gene expression, metabolomics, diet, and metabolic traits highlighted VF-DMPs located in 9 genes with strong relevance to metabolic disease mechanisms, with replication of signals in FASN, SREBF1, TAGLN2, PC and CFAP410. PC methylation showed evidence for mediating effects of diet on VF. FASN DNA methylation exhibited putative causal effects on VF that were also strongly associated with insulin resistance and methylation levels in FASN better classified insulin resistance (AUC=0.91) than BMI or VF alone. Conclusions Our findings help characterise the adiposity-associated methylation signature of SAT, with insights for metabolic disease risk

Adiposity, breast density, and breast cancer risk ::epidemiological and biological considerations

Excess total body fat and abdominal adipose tissue are recognized risk factors for metabolic diseases but also for some types of cancers, including breast cancer. Several biological mechanisms in connection with local and systemic effects of adiposity are believed to be implicated in breast cancer development, and may involve breast fat. Breast adipose tissue can be studied through mammography by looking at breast density features such as the nondense area mainly composed of fat, or the percent breast density, which is the proportion of fibroglandular tissue in relation to fat. The relation between adiposity, breast density features, and breast cancer is complex. Studies suggest a paradoxical association as adiposity and absolute nondense area correlate positively with each other, but in contrast to adiposity, absolute nondense area seems to be associated negatively with breast cancer risk. As breast density is one of the strongest risk factors for breast cancer, it is therefore critical to understand how these factors interrelate. In this review, we discuss these relations by first presenting how adiposity measurements and breast density features are linked to breast cancer risk. Then, we used a systematic approach to capture the literature to review the relation between adiposity and breast density features. Finally, the role of adipose tissue in carcinogenesis is discussed briefly from a biological perspective

Metallothionein 2a gene expression is increased in subcutaneous adipose tissue of type 2 diabetic patients

STUDY BACKGROUND: Insulin resistance plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine the Mt2a gene expression levels in adipose tissues from diabetic patients and the effect of Mt treatment on adipocyte insulin sensitivity. METHODS: Samples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNF&alpha; (10 ng/ml, 72 h) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein. RESULTS: We found that the Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to that of lean (p=0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNF&alpha; increased Mt2a mRNA levels (p=3&times;10-4) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p=8&times;10-4) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein. CONCLUSIONS: These data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes

Complement Receptors C5aR and C5L2 Are Associated with Metabolic Profile, Sex Hormones, and Liver Enzymes in Obese Women Pre- and Postbariatric Surgery

Objective. Obesity is associated with metabolic dysfunction with sex differences and chronic, low-grade inflammation. We proposed that hepatic expression of immune complement C3 related receptors (C3aR, C5aR, and C5L2) would be associated with pre- or postmenopausal status and metabolic profile in severely obese women. We hypothesized that C5L2/C5aR ratio, potentially influencing the ASP/C5L2 metabolic versus C5a/C5aR immune response, would predict metabolic profiles after weight loss surgery. Materials and Methods. Fasting plasma (hormone, lipid, and enzyme analysis) and liver biopsies (RT-PCR gene expression) were obtained from 91 women during surgery. Results. Hepatic C5L2 mRNA expression was elevated in pre- versus postmenopausal women (P<0.01) and correlated positively with circulating estradiol, estrone, ApoB, ApoA1, ApoA1/B, waist circumference, age, and LDL-C (all P<0.05). While plasma ASP was lower in pre- versus postmenopausal women (P<0.01), the hepatic C5L2/C5aR mRNA ratio was increased (P<0.001) and correlated positively with estrone (P<0.01) and estradiol (P<0.001) and negatively with circulating ApoB and liver enzymes ALT, AST, and GGT (all P<0.05). Over 12 months postoperatively, liver enzymes in low C5L2/C5aR mRNA ratio group remained higher (ALP and ALT, P<0.05, AST and GGT, P<0.001 2-way-ANOVA). Conclusion. C5L2-C5aR association with other mediators including estrogens may contribute to hepatic metabolic and inflammatory function