Co-methylated genes in different adipose depots of pig are associated with metabolic, inflammatory and immune processes

It is well established that the metabolic risk factors of obesity and its comorbidities are more attributed to adipose tissue distribution rather than total adipose mass. Since emerging evidence suggests that epigenetic regulation plays an important role in the aetiology of obesity, we conducted a genome-wide methylation analysis on eight different adipose depots of three pig breeds living within comparable environments but displaying distinct fat level using methylated DNA immunoprecipitation sequencing. We aimed to investigate the systematic association between anatomical location-specific DNA methylation status of different adipose depots and obesity-related phenotypes. We show here that compared to subcutaneous adipose tissues which primarily modulate metabolic indicators, visceral adipose tissues and intermuscular adipose tissue, which are the metabolic risk factors of obesity, are primarily associated with impaired inflammatory and immune responses. This study presents epigenetic evidence for functionally relevant methylation differences between different adipose depots.     

Omental and subcutaneous adipose tissue steroid levels in obese men

We examined plasma and fat tissue sex steroid levels in a sample of 28 men aged 24.8-62.2 years (average BMI value of 46.3 +/- 12.7 kg/m(2)). Abdominal adipose tissue biopsies were obtained during general or obesity surgery. Omental and subcutaneous adipose tissue steroid levels were measured by gas chromatography and chemical ionization mass spectrometry after appropriate extraction procedures. BMI and waist circumference were negatively correlated with plasma testosterone (r = -0.49 and -0.50, respectively, p < 0.01) and dihydrotestosterone (r = -0.58 and -0.56, respectively, p < 0.01), and positively associated with estrone levels (r = 0.64 and 0.62, respectively, p < 0.001). Regional differences in adipose tissue steroid levels were observed for dihydrotestosterone (p < 0.005), androstenedione (p < 0.0001) and dehydroepiandrosterone levels (p < 0.05), which were all significantly more concentrated in omental versus subcutaneous fat. Positive significant associations were found between circulating level of a steroid and its concentration in omental and subcutaneous adipose tissue, for estrone (r = 0.72 and 0.57, respectively, p < 0.01), testosterone (r = 0.66 and 0.58, respectively, p < 0.01) and dihydrotestosterone (r = 0.58 and 0.45, respectively, p < 0.05). Positive correlations were observed between plasma dehydroepiandrosterone-sulfate and omental (r = 0.56, p < 0.01) as well as subcutaneous adipose tissue dehydroepiandrosterone level (r = 0.38, p = 0.05). Positive significant associations were found between omental adipocyte responsiveness to positive lipolytic stimuli (isoproterenol, dibutyryl cyclic AMP and forskolin) and plasma or omental fat tissue androgen levels. In conclusion, although plasma androgen or estrogen levels are strong correlates of adipose tissue steroid content both in the omental and subcutaneous fat depots, regional differences may be observed. Androgen concentration differences in omental versus subcutaneous adipose tissue suggest a depot-specific impact of these hormones on adipocyte function and metabolism.     

Subdivision of the Subcutaneous Adipose Tissue Compartment and Lipid‐Lipoprotein Levels in Women

Objective: The aim of this study was to compare the relative importance of computed tomography‐measured abdominal fat compartment areas, including adipose tissue located posterior to the subcutaneous Fascia, in predicting plasma lipid‐lipoprotein alterations. Research Methods and Procedures: Areas of visceral as well as subcutaneous deep and superficial abdominal adipose tissue were measured by computed tomography in a sample of 66 healthy women, ages 37 to 60 years, for whom a detailed lipid‐lipoprotein profile was available. Results: Strong significant associations were observed between visceral adipose tissue area and most variables of the lipid‐lipoprotein profile (r = ?0.25, p < 0.05 to 0.62, p < 0.0001). Measures of hepatic lipoprotein synthesis such as very‐low‐density lipoprotein‐triglyceride and cholesterol content as well as total and very‐low‐density lipoprotein‐apolipoprotein B levels were also strongly associated with visceral adipose tissue area (r = 0.57, 0.57, 0.61, and 0.62, respectively, p < 0.0001). Significant associations were found between these variables and the deep subcutaneous adipose tissue area or DXA‐measured total body fat mass. However, the correlation coefficients were of lower magnitude compared to those with visceral adipose tissue area. Multivariate regression analyses demonstrated that visceral adipose tissue area was the strongest predictor of lipid‐lipoprotein profile variables (7% to 48% explained variance, 0.02 ≥ p ≤ 0.0001). Discussion: Although previous studies have generated controversial data as to which abdominal adipose tissue compartment was more closely associated with insulin resistance, our results suggest that visceral adipose tissue area is a stronger correlate of other obesity‐related outcomes such as lipid‐lipoprotein alterations.     

Vaspin gene expression in human adipose tissue: association with obesity and type 2 diabetes

Recently, vaspin was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose tissue in a rat model of type 2 diabetes. In this study, we examined whether vaspin mRNA expression is a marker of visceral obesity and correlates with anthropometric and metabolic parameters in paired samples of visceral and subcutaneous adipose tissue from 196 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance. Vaspin mRNA expression was only detectable in 23% of the visceral and in 15% of the subcutaneous (SC) adipose tissue samples. Vaspin mRNA expression was not detectable in lean subjects (BMI<25) and was more frequently detected in patients with type 2 diabetes. No significant correlations were found between visceral vaspin gene expression and visceral fat area or SC vaspin expression. However, visceral vaspin expression significantly correlates with BMI, % body fat, and 2 h OGTT plasma glucose. Subcutaneous vaspin mRNA expression is significantly correlated with WHR, fasting plasma insulin concentration, and glucose infusion rate during steady state of an euglycemic-hyperinsulinemic clamp. Multivariate linear regression analysis revealed % body fat as strongest predictor of visceral vaspin and insulin sensitivity as strongest determinant of SC vaspin mRNA expression. In conclusion, our data indicate that induction of human vaspin mRNA expression in adipose tissue is regulated in a fat depot-specific manner and could be associated with parameters of obesity, insulin resistance, and glucose metabolism.     

Associations between Ultrasound Measures of Abdominal Fat Distribution and Indices of Glucose Metabolism in a Population at High Risk of Type 2 Diabetes: The ADDITION-PRO Study

Aims

Visceral adipose tissue measured by CT or MRI is strongly associated with an adverse metabolic risk profile. We assessed whether similar associations can be found with ultrasonography, by quantifying the strength of the relationship between different measures of obesity and indices of glucose metabolism in a population at high risk of type 2 diabetes.

Methods

A cross-sectional analysis of 1342 participants of the ADDITION-PRO study. We measured visceral adipose tissue and subcutaneous adipose tissue with ultrasonography, anthropometrics and body fat percentage by bioelectrical impedance. Indices of glucose metabolism were derived from a three point oral glucose tolerance test. Linear regression of obesity measures on indices of glucose metabolism was performed.

Results

Mean age was 66.2 years, BMI 26.9kg/m², subcutaneous adipose tissue 2.5cm and visceral adipose tissue 8.0cm. All measures of obesity were positively associated with indicators of glycaemia and inversely associated with indicators of insulin sensitivity. Associations were of equivalent magnitude except for subcutaneous adipose tissue and the visceral/subcutaneous adipose tissue ratio, which showed weaker associations. One standard deviation difference in BMI, visceral adipose tissue, waist circumference, waist/height ratio and body fat percentage corresponded approximately to 0.2mmol/l higher fasting glucose, 0.7mmol/l higher 2-hr glucose, 0.06-0.1% higher HbA1c, 30 % lower HOMA index of insulin sensitivity, 20% lower Gutt’s index of insulin sensitivity, and 100 unit higher Stumvoll’s index of beta-cell function. After adjustment for waist circumference visceral adipose tissue was still significantly associated with glucose intolerance and insulin resistance, whereas there was a trend towards inverse or no associations with subcutaneous adipose tissue. After adjustment, a 1cm increase in visceral adipose tissue was associated with ~5% lower insulin sensitivity (p≤0.0004) and ~0.18mmol/l higher 2-hr glucose (p≤0.001).

Conclusion

Visceral and subcutaneous adipose tissue assessed by ultrasonography are significantly associated with glucose metabolism, even after adjustment for other measures of obesity.     

Characterization and comparison of adipose tissue‐derived cells from human subcutaneous and omental adipose tissues

Different fat depots contribute differently to disease and function. These differences may be due to the regional variation in cell types and inherent properties of fat cell progenitors. To address the differences of cell types in the adipose tissue from different depots, the phenotypes of freshly isolated adipose tissue‐derived cells (ATDCs) from subcutaneous (SC) and omental (OM) adipose tissues were compared using flow cytometry. Our results showed that CD31^?CD34⁺CD45^?CD90^‐CD105^?CD146⁺ population, containing vascular smooth muscle cells and pericytes, was specifically defined in the SC adipose tissue while no such population was observed in OM adipose tissue. On the other hand, CD31^?CD34⁺CD45^?CD90^?CD105^?CD146^? population, which is an undefined cell population, were found solely in OM adipose tissue. Overall, the SC adipose tissue contained more ATDCs than OM adipose tissue, while OM adipose tissue contained more blood‐derived cells. Regarding to the inherent properties of fat cell progenitors from the two depots, adipose‐derived stem cells (ADSCs) from SC had higher capacity to differentiate into both adipogenic and osteogenic lineages than those from OM, regardless of that the proliferation rates of ADSCs from both depots were similar. The higher differentiation capacity of ADSCs from SC adipose tissue suggests that SC tissue is more suitable cell source for regenerative medicine than OM adipose tissue. Copyright © 2009 John Wiley & Sons, Ltd.     

Body Compartment and Subcutaneous Adipose Tissue Distribution - Risk Factor Patterns in Obese Subjects

The purpose of this study was to investigate whether upper body obesity and/or visceral obesity are related to cardiovascular risk factors among severely obese subjects, phenomena that have previously been reported in more heterogeneous body weight distri -buttons. 2450 severely obese men and women aged 37 to 59 years, with a body mass index of 39 ± 4.5 kg/m² (mean ± SD) were examined cross-sectionally. Eight cardiovascular risk factors were studied in relation. to the following body composition indicators: four trunk and three limb circumferences, along with weight, height and sagittal trunk diameter. From the latter three measurements lean body mass (LBM, i.e., the non-adipose tissue mass) and the masses of subcutaneous and visceral adipose tissue were estimated by using sex-specific prediction equations previously calibrated by computed tomography. Two risk factor patterns could be distinguished: 1. One body compartment- risk factor pattern in which the subcutaneous adipose tissue (AT) mass and, in particular, the visceral AT mass were positively related to most risk factors while the lean body mass was negatively related to some risk factors. 2. One subcutaneous adipose tissue distribution- risk factor pattern in which the neck circumference was positively and the thigh circumference negatively related to several risk factors. It is concluded that lean body mass (LBM), visceral and subcutaneous adipose tissue masses as well as neck and thigh circumferences, used as indices of subcutaneous adipose tissue distribution, are independently related to cardiovascular risk factors in severely obese men and women.     

The contribution of visceral fat to improved insulin signaling in Ames dwarf mice

Ames dwarf (Prop1^df, df/df) mice are characterized by growth hormone (GH), prolactin, and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti‐inflammatory adiponectin are increased in df/df mice, while pro‐inflammatory IL‐6 is decreased in plasma and epididymal fat. This represents an important shift in the balance between pro‐ and anti‐inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long‐living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals.     

Relationships Between Changes in Body Composition and Changes in Cardiovascular Risk Factors: The SOS Intervention Study

SJÖSTRÖM, C DAVID, LAUREN LISSNER, LARS SJÖSTROM. Relationships between changes in body composition and changes in cardiovascular risk factors: The SOS Intervention Study. Relationships between 2-year changes in body composition (estimated from computed tomography-validated anthropometry based on sagittal trunk diameter, weight, and height), adipose tissue (AT) distribution, and cardiovascular risk factors (blood pressure, lipids, glucose, insulin, uric acid) were examined in 842 treated adults with severe obesity with weight changes from ?95. 5 to +30. 6 kg. Although the change (Δ) of visceral AT mass (expressed in % total AT) for a given change in body mass index (ΔBMI) was 6-fold larger in men than in women, Δwaist and Δwaist/hip were similar in both sexes. In men, risk factor changes were similarly related to Awaist, Abodyweight, and ΔBMI, whereas in women, Δbodyweight seemed to be the single independent variable with the highest explanatory power. In multivariate regressions adjusted for ΔBMI and baseline conditions, Δvisceral AT mass was more strongly associated with risk factor changes than were Δwaist and ?waist/hip. When using a three-compartment model (lean body mass, subcutaneous and visceral AT masses) plus neck and thigh girths (indicators of subcutaneous AT distribution), risk factor changes were related both to ?subcutaneous and ?visceral AT masses but not to Δlean body mass. In agreement with cross-sectional findings, Δneck was positively and Δthigh was negatively related to some risk factor changes. Thus, the use of waist as a single risk factor indicator seems less effective for epidemiological studies than the simple anthropometric measures presented here, which are able to separate the effects of visceral AT mass, subcutaneous AT mass, and subcutaneous AT distribution on metabolic parameters under both cross-sectional and longitudinal conditions.     

Age-associated adipose tissue inflammation promotes monocyte chemotaxis and enhances atherosclerosis

Although aging enhances atherosclerosis, we do not know if this occurs via alterations in circulating immune cells, lipid metabolism, vasculature, or adipose tissue. Here, we examined whether aging exerts a direct pro-atherogenic effect on adipose tissue in mice. After demonstrating that aging augmented the inflammatory profile of visceral but not subcutaneous adipose tissue, we transplanted visceral fat from young or aged mice onto the right carotid artery of Ldlr^−/− recipients. Aged fat transplants not only increased atherosclerotic plaque size with increased macrophage numbers in the adjacent carotid artery, but also in distal vascular territories, indicating that aging of the adipose tissue enhances atherosclerosis via secreted factors. By depleting macrophages from the visceral fat, we identified that adipose tissue macrophages are major contributors of the secreted factors. To identify these inflammatory factors, we found that aged fat transplants secreted increased levels of the inflammatory mediators TNFα, CXCL2, and CCL2, which synergized to promote monocyte chemotaxis. Importantly, the combined blockade of these inflammatory mediators impeded the ability of aged fat transplants to enhance atherosclerosis. In conclusion, our study reveals that aging enhances atherosclerosis via increased inflammation of visceral fat. Our study suggests that future therapies targeting the visceral fat may reduce atherosclerosis disease burden in the expanding older population.     

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Obesity is accompanied by adipocyte death and accumulation of macrophages and mast cells in expanding adipose tissues. Considering the differences in biological behavior of fat found in different anatomical locations, we explored the distribution of mast cells, solitary macrophages, and crown-like structures (CLS), the surrogates for dead adipocytes, in subcutaneous and abdominal visceral fat of lean and diet-induced obese C57BL/6 mice. In fat depots of lean mice, mast cells were far less prevalent than solitary macrophages. Subcutaneous fat contained more mast cells, but fewer solitary macrophages and CLS, than visceral fat. Whereas no significant change in mast cell density of subcutaneous fat was observed, obesity was accompanied by a substantial increase in mast cells in visceral fat. CLS became prevalent in visceral fat of obese mice, and the distribution paralleled mast cells. Adipose tissue mast cells contained and released preformed TNF-α, the cytokine implicated in the pathogenesis of obesity-linked insulin resistance. In summary, subcutaneous fat differed from visceral fat by immune cell composition and a lower prevalence of CLS both in lean and obese mice. The increase in mast cells in visceral fat of obese mice suggests their role in the pathogenesis of obesity and insulin resistance.     

猪脂肪组织和原代脂肪细胞中GPR43基因的转录表达规律

根据GenBank已发表的人、小鼠及大鼠GPR43(G protein-coupled receptor 43)基因序列, 设计并合成一对引物, RT-PCR扩增获得猪GPR43基因cDNA, 并利用PCR技术检测该基因在不同猪种、不同发育阶段、不同部位脂肪组织及原代脂肪细胞中的转录表达规律。结果显示, 成功克隆猪GPR43 cDNA片段, 长度为486 bp (GenBank登陆号为EU122439); 同源性分析发现, 猪GPR43与人、小鼠和大鼠同源性达83%以上; GPR43 mRNA表达量在脂肪型猪种上显著高于瘦肉型猪种, 随月龄增长表达量逐渐上升, 且皮下脂肪表达量较内脏脂肪高; 在猪前体脂肪细胞诱导分化过程中, GPR43 mRNA表达量呈时间依赖性升高。揭示GPR43 mRNA表达与猪肥胖程度、年龄、脂肪沉积部位以及脂肪细胞分化程度密切相关。     

妊娠期糖尿病血清和脂肪组织内脂素的表达

目的:探讨妊娠期糖尿病孕妇内脂素水平与糖代谢的关系.方法:检测血清中内脂素、FIN、FIG水平,计算HOMA-IR,用RT-PCR法检测脂肪组织中内脂素mRNA的表达.结果:(1)妊娠期糖尿病组孕妇血清内脂素、FPG、HOMA-IR、FIN明显高于对照组.(2)妊娠期糖尿病组孕妇内脏脂肪组织中的内脂素的表达明显高于对照组,且妊娠期糖尿病组孕妇内脏组织中内脂素的表达明显高于表皮脂肪组织.(3)血清中内脂素的水平与内脏脂肪组织及HOMA-IR呈正相关.结论:妊娠期糖尿病孕妇脂肪组织中内脂素表达上调,导致血液循环中内脂素水平升高,参与GDM孕妇血糖调节.     

The Accumulation of Visceral Adipose Tissue may be Influenced by Intra-Abdominal Temperature

Despite the established link between visceral obesity and major chronic diseases, little is known about physiologic factors that directly and specifically lead to the accumulation of visceral fat. I hypothesize that reduced intra-abdominal temperature might be a physical factor underlying the partitioning of adipose tissue to the intra-abdominal region rather than the periphery. The hypothesis is supported by biochemical reports that rat and bovine lipoprotein lipase have increased activity when incubated at lower temperatures. Persons exercising in cool water have been found to preserve subcutaneous fat whereas comparable exercise without local cooling results in subcutaneous fat loss. Pima Indians, a group that commonly acquires extreme levels of visceral fat, have been found to have lower intraabdominal temperatures during sleep than weight-matched European-Americans. In a study of four young men and four young women, I have noted that mean intra-abdominal basal temperatures were higher for women than men (36.51 ± 0.18°C vs. 35.91 ± 0.11°C; p = .0014). Since the men are more likely to acquire visceral obesity at later age, this also provides support for my hypothesis. Investigators might wish to examine further the temperature dependence of adipose-tissue lipoprotein lipase, the temperature variation between sites of adipose tissue, and the effects of foods, physical activities, smoking and drugs on localized body temperature.     

京尼平对小鼠棕色和白色脂肪组织UCP1表达的影响

目的:棕色脂肪组织活化和白色脂肪组织棕化是改善减肥的良好策略。本研究利用冷刺激作为阳性对照,观察京尼平对小鼠脂肪组织活化与棕化的作用。方法:8周龄雄性C57BL/6J小鼠30只,随机分为正常对照组、京尼平组、冷刺激组, 每组10只。京尼平组小鼠腹腔注射给予京尼平处理(15 mg/(kg·d),连续9 d),对照组用生理盐水处理,冷刺激组小鼠在室温(22℃±2℃)下处理4 d后,置于4℃环境中进行冷刺激处理5 d(24 h/d)。检测各组小鼠每天摄食量、体重和体温变化,取肩胛下区、腹股沟区及附睾周围部分脂肪组织观察形态学的变化,测定棕色脂肪组织、皮下白色脂肪组织以及内脏白色脂肪组织解偶联蛋白1(UCP1)的表达。结果:与正常对照组相比,京尼平组小鼠白色脂肪湿重下降16%,冷刺激组下降28%,均有明显差异(P＜0.05);京尼平组和冷刺激组白色脂肪组织颜色变深,HE染色显示脂肪细胞内的脂滴变小,数量增加;京尼平组小鼠的皮下、内脏白色脂肪组织和棕色3种脂肪组织中的UCP1表达量均明显增加(P＜0.05)。结论:京尼平通过上调UCP1的表达促进棕色脂肪组织活化和白色脂肪组织棕化,此效应是京尼平降脂减轻体重的作用机制之一。     

Validation of a free software for unsupervised assessment of abdominal fat in MRI

PurposeTo demonstrate the accuracy of an unsupervised (fully automated) software for fat segmentation in magnetic resonance imaging. The proposed software is a freeware solution developed in ImageJ that enables the quantification of metabolically different adipose tissues in large cohort studies.MethodsThe lumbar part of the abdomen (19 cm in craniocaudal direction, centered in L3) of eleven healthy volunteers (age range: 21–46 years, BMI range: 21.7–31.6 kg/m²) was examined in a breath hold on expiration with a GE T1 Dixon sequence. Single-slice and volumetric data were considered for each subject. The results of the visceral and subcutaneous adipose tissue assessments obtained by the unsupervised software were compared to supervised segmentations of reference. The associated statistical analysis included Pearson correlations, Bland-Altman plots and volumetric differences (VD_%).ResultsValues calculated by the unsupervised software significantly correlated with corresponding supervised segmentations of reference for both subcutaneous adipose tissue – SAT (R = 0.9996, p < 0.001) and visceral adipose tissue – VAT (R = 0.995, p < 0.001). Bland-Altman plots showed the absence of systematic errors and a limited spread of the differences. In the single-slice analysis, VD_% were (1.6 ± 2.9)% for SAT and (4.9 ± 6.9)% for VAT. In the volumetric analysis, VD_% were (1.3 ± 0.9)% for SAT and (2.9 ± 2.7)% for VAT.ConclusionsThe developed software is capable of segmenting the metabolically different adipose tissues with a high degree of accuracy. This free add-on software for ImageJ can easily have a widespread and enable large-scale population studies regarding the adipose tissue and its related diseases.