Increased visceral adipose tissue is associated with increased resting heart rate in patients with manifest vascular disease

Abdominal obesity is characterized by sympathetic nerve activation (SNA), probably mediated by elevated insulin and leptin levels. Resting heart rate (RHR) is a marker of sympathetic tone, and independently associated with cardiovascular events and death in various populations. We investigated and quantified the relation between visceral adipose tissue (VAT) and RHR in patients with vascular disease. In 3,723 patients with manifest vascular disease, visceral and subcutaneous fat tissue was measured with ultrasonography. RHR was obtained from an electrocardiogram (ECG). The association between quartiles of VAT and RHR was quantified using linear regression analysis with adjustments for potential confounding factors. Separate analyses were performed for men and women and for location of vascular disease. Visceral fat was categorized into sex-pooled quartiles (Q) ranging from 2.7-8.0 cm in Q1 (reference) to 9.4-20.6 cm in Q4. High visceral fat thickness was associated with increased RHR, in men (Q4 vs. Q1, β = 4.36; 95% confidence interval (CI) = 3.11-5.61) and women (β = 1.48; 95% CI = -0.70 to 3.66), after full adjustment. Waist circumference and BMI had a significant relation with RHR in men (β = 3.51; 95% CI = 2.21-4.81 and β = 2.80; 95% CI = 1.51-4.08, respectively) but these relations were smaller and not significant in women (β = 0.71; 95% CI = -1.44 to 2.85 and β = 0.24; 95% CI = -1.90 to 2.37, respectively). There was no relation between subcutaneous fat and RHR in men and women. The relation between visceral fat and RHR was similar in patients with different locations of vascular diseases. Increased visceral fat is associated with increased RHR in male and female patients with vascular disease, independent of the location.     

Visfatin mRNA expression in human subcutaneous adipose tissue is regulated by exercise

Visfatin [pre-beta-cell colony-enhancing factor (PBEF)] is a novel adipokine that is produced by adipose tissue, skeletal muscle, and liver and has insulin-mimetic actions. Regular exercise enhances insulin sensitivity. In the present study, we therefore examined visfatin mRNA expression in abdominal subcutaneous adipose tissue and skeletal muscle biopsies obtained from healthy young men at time points 0, 3, 4.5, 6, 9, and 24 h in relation to either 3 h of ergometer cycle exercise at 60% of Vo(2 max) or rest. Adipose tissue visfatin mRNA expression increased threefold at the time points 3, 4.5, and 6 h in response to exercise (n = 8) compared with preexercise samples and compared with the resting control group (n = 7, P = 0.001). Visfatin mRNA expression in skeletal muscle was not influenced by exercise. The exercise-induced increase in adipose tissue visfatin was, however, not accompanied by elevated levels of plasma visfatin. Recombinant human IL-6 infusion to mimic the exercise-induced IL-6 response (n = 6) had no effect on visfatin mRNA expression in adipose tissue compared with the effect of placebo infusion (n = 6). The finding that exercise enhances subcutaneous adipose tissue visfatin mRNA expression suggests that visfatin has a local metabolic role in the recovery period following exercise.     

Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

As a part of aging there are known to be numerous alterations which occur in multiple tissues of the body, and the focus of this study was to determine the extent to which oxidative stress and hypoxia occur during adipose tissue aging. In our studies we demonstrate for the first time that aging is associated with both hypoxia (38% reduction in oxygen levels, Po(2) 21.7 mmHg) and increases reactive oxygen species in visceral fat depots of aging male C57Bl/6 mice. Interestingly, aging visceral fat depots were observed to have significantly less change in the expression of genes involved in redox regulation compared with aging subcutaneous fat tissue. Exposure of 3T3-L1 adipocytes to the levels of hypoxia observed in aging adipose tissue was sufficient to alter multiple aspects of adipose biology inducing increased levels of in insulin-stimulated glucose uptake and decreased lipid content. Taken together, these data demonstrate that hypoxia and increased levels of reactive oxygen species occur in aging adipose tissue, highlighting the potential for these two stressors as potential modulators of adipose dysfunction during aging.     

Argonaute-2 is associated to brown adipose tissue activation

MicroRNAs (miRNAs) are important modulators of thermogenic brown adipose tissue (BAT). They have been involved in its differentiation and hence its functioning. While different regulators of the miRNA machinery have been shown to be essential for BAT differentiation, little is known about their implication in BAT activation. The aim of this work was to evaluate the role of AGO2, the chief miRNA mediator, in BAT activation.We took advantage of two non-genetic models of BAT activation to analyze the miRNA machinery and miRNA expression in BAT. We used principal component analysis (PCA) to obtain an overview of miRNA expression according to the BAT activation state. In vitro, we examined AGO2 expression during brown adipocyte differentiation and activation. Finally, we downregulated AGO2 to reveal its potential role in the thermogenic function of brown adipocytes.PCA analysis allowed to cluster animals on their miRNA signature in active BAT. Moreover, hierarchical clustering showed a positive correlation between global upregulation of miRNA expression and active BAT. Consistently, the miRNA machinery, particularly AGO2, was upregulated in vivo in active BAT and in vitro in mature brown adipocytes. Finally, the partial loss-of-function of AGO2 in mature brown adipocytes is sufficient to lead to a diminished expression of UCP1 associated to a decreased uncoupled respiration.Therefore, our study shows the potential contribution of AGO2 in BAT activation. Since BAT is a calorie-burning tissue these data have a translational potential in terms of therapeutic target in the field of altered fuel homeostasis associated to obesity and diabetes.     

Intra-abdominal adipose tissue is independently associated with sex-hormone binding globulin in premenopausal women

Lower serum concentrations of sex-hormone binding globulin (SHBG) are associated with increased risk for several obesity-related diseases in women including hormone-sensitive cancers, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Previous investigations have reported that body composition, specifically central obesity, and/or higher insulin concentrations are key factors associated with lower SHBG in overweight and obese women; however, these studies were limited by their cross-sectional design. We hypothesized that intra-abdominal adipose tissue (IAAT), a fat depot linked with an abnormal metabolic profile, is inversely and independently associated with SHBG. Therefore, we determined the longitudinal associations among SHBG, insulin, and IAAT in 107 premenopausal women enrolled in a weight loss study. Overweight (BMI 27-30 kg/m(2)) women were weight reduced until BMI of ≤ 24 was achieved. Body composition and IAAT were measured at baseline and after weight loss with dual-energy X-ray absorptiometry and computed tomography, respectively. Serum concentrations of insulin and SHBG were determined. Paired t-test showed that insulin and IAAT decreased significantly and SHBG increased significantly following weight loss (P < 0.0001 for all). Simple correlations from baseline showed no association with insulin and SHBG (r = -0.142, P = 0.143) and a significant inverse association between IAAT and SHBG (r = -0.43, P < 0.0001). Repeated measures mixed-model showed that after adjusting for age and time (weight loss), IAAT was significantly inversely associated with SHBG (P = 0.0002) and there was no association with insulin and SHBG (P = 0.180). We conclude that SHBG concentrations are influenced by IAAT and not insulin in premenopausal women.     

Proteome differences associated with fat accumulation in bovine subcutaneous adipose tissues

Background  

The fat components of red meat products have been of interest to researchers due to the health aspects of excess fat consumption by humans. We hypothesized that differences in protein expression have an impact on adipose tissue formation during beef cattle development and growth. Therefore, in this study we evaluated the differences in the discernable proteome of subcutaneous adipose tissues of 35 beef crossbred steers [Charolais × Red Angus (CHAR) (n = 13) and Hereford × Angus (HEAN) (n = 22)] with different back fat (BF) thicknesses. The goal was to identify specific protein markers that could be associated with adipose tissue formation in beef cows.     

Ultrasonic measurements of subcutaneous adipose tissue thickness in man

Subcutaneous adipose tissue thickness (SCATT) has for many years been measured using skinfold calipers, but calipers have several disadvantages, not least that they compress the skinfold. Measuring SCATT using ultrasound was validated by comparing thicknesses at 12 sites with soft-tissue radiographs in 24 adults and with depth gauge measurements on a cadaver. Correlation coefficients ranged from 0.87 to 0.99, and the regression statistics showed no significant difference between ultrasound and the other procedures. The standard errors of estimate of body density from SCATT measured by calipers and ultrasound in 63 young men was +/- 7.8 and 7.3 kg X m-3, respectively. Although problems in the identification of the adipose tissue-muscle interface can arise, ultrasound is a viable alternative to skinfold calipers and is to be preferred when measuring uncompressed SCATT.     

Birth weight is inversely associated with central adipose tissue in healthy children and adolescents

Objective: Previous studies have explored the association between birth weight and excess childhood body fat, but few have used precise measures of body composition, leading to equivocal and sometimes contradictory results. Research Methods and Procedures: Subjects included 101 children who underwent DXA measurements between 1995 and 2000. Birth weight and gestational age were assessed using maternal recall. Multiple linear regression analysis was used to determine the relationship between birth weight and the following four outcome variables: total fat mass (FM), truncal fat mass (TrFM), percentage body fat (%BF), and TrFM adjusted for FM (TrFMadj), controlling for current weight and Tanner stage. Results: The mean age of the children studied was 12.9 ± 2.4 years, and the mean birth weight reported by subjects’ mothers was 3.3 ± 0.5 kg. The FM and TrFM were 12.8 ± 8.7 kg and 5.1 ± 4.1 kg, respectively, and the mean %BF was 22.9 ± 10.3%. Birth weight was a significant predictor of FM (p = 0.02) and %BF (p = 0.038). However, birth weight adjusted for gestational age (BWTadj) was a significant (p = 0.03) negative predictor of TrFMadj, independently of race, sex, Tanner stage, and current weight. Discussion: These results provide evidence that, even in childhood and adolescence, a higher birth weight is associated with higher FM and %BF, while a low birth weight is associated with TrFM, adjusted for FM.     

LysoPC-acyl C16:0 is associated with brown adipose tissue activity in men

Introduction

Brown adipose tissue (BAT) recently emerged as a potential therapeutic target in the treatment of obesity and associated disorders due to its fat-burning capacity. The current gold standard in assessing BAT activity is [¹⁸F]FDG PET-CT scan, which has severe limitations including radiation exposure, being expensive, and being labor-intensive. Therefore, indirect markers are needed of human BAT activity and volume.

Objective

We aimed to identify metabolites in serum that are associated with BAT volume and activity in men.

Methods

We assessed 163 metabolites in fasted serum of a cohort of twenty-two healthy lean men (age 24.1 (21.7–26.6) years, BMI 22.1 (20.5–23.4) kg/m²) who subsequently underwent a cold-induced [¹⁸F]FDG PET-CT scan to assess BAT volume and activity. In addition, we included three replication cohorts consisting of in total thirty-seven healthy lean men that were similar with respect to age and BMI compared to the discovery cohort.

Results

After correction for multiple testing, fasting concentrations of lysophosphatidylcholine-acyl (LysoPC-acyl) C16:1, LysoPC-acyl C16:0 and phosphatidylcholine-diacyl C32:1 showed strong positive correlations with BAT volume (β=?116 (85–148) mL, R²?=?0.81, p?=?4.6?×?10^?7 _; β?=?79 (93–119) mL, R²?=?0.57, p?=?5.9?×?10^?4 and β=?91 (40–141) mL, R²?=?0.52, p?=?1.0?×?10^?3, respectively) as well as with BAT activity (β=?0.20 (0.11–0.29) g/mL, R²?=?0.59, p?=?1.9?×?10^?4; β?=?0.15 (0.06–0.23) g/mL, R²?=?0.47, p?=?2.0?×?10^?3 and β=?0.13 (0.01–0.25) g/mL, R²?=?0.28, p?=?0.04, respectively). When tested in three independent replication cohorts (total n?=?37), the association remained significant between LysoPC-acyl C16:0 and BAT activity in a pooled analysis (β=?0.15 (0.07–0.23) g/mL, R²?=?0.08, p?=?4.2?×?10^?4).

Conclusions

LysoPC-acyl C16:0 is associated with BAT activity in men. Since BAT is regarded as a promising tool in the battle against obesity and related disorders, the identification of such a noninvasive marker is highly relevant.

     

Decreased serum creatinine concentration is associated with short telomeres of adipose tissue cells

Decreased serum creatinine concentration has been recently described to constitute a new risk factor of type 2 diabetes. Increased free radicals have been consistently associated with decreased serum creatinine and with cellular senescence. Telomere length is considered as a biological marker for senescence. We aimed to study the association of telomere length with serum creatinine. Telomere length of subcutaneous adipose tissue cells was measured in a sample of obese and nonobese subjects (n = 49). Telomere length of subcutaneous adipose tissue cells was positively associated with serum creatinine (r = 0.40, P = 0.004), i.e., the lower the telomere length, the lower the serum creatinine, but not with glomerular filtration rate (GFR). In addition, telomere length was negatively associated with BMI (r = -0.45, P = 0.001) and systolic blood pressure (r = -0.41, P = 0.003). In a multiple linear regression analysis, BMI (P = 0.005), systolic blood pressure (P = 0.01) and telomere length (P = 0.03) independently contributed to 37% of serum creatinine variance after controlling for sex and age. In conclusion, the association of serum creatinine with a marker of cellular senescence suggests an underlying mechanism influencing both decreased serum creatinine and increased risk of type 2 diabetes.     

Melanoma and subcutaneous adipose tissue: Role of peritumoral adipokines in disease characterization and prognosis

In the last decades, the concept of adipose organ has emerged, giving adipose tissue an active endocrine and immunologic function through the secretion of multiple cytokines and chemokines that seem to be implicated in the development and progression of several cancer, including cutaneous melanoma. In this pilot experimental study, we analyzed the expression in the peritumor subcutaneous adipose tissue of the most significant adipokines involved in the processes of carcinogenesis and metastasis in a population of melanoma patients and in two control groups composed of melanocytic nevi and epidermoid cysts, respectively. We correlated the results obtained with the main disease prognostic factors observing a statistically significant increase in the expression of PAI1, LEP, CXCL1, NAMPT, and TNF-α at the level of the peritumor tissue of the melanoma samples compared to the control groups and a correlation of the same with the histopathological prognostic factor of melanoma. Our preliminary study shows that the overexpression of PAI1, LEP, CXCL1, NAMPT, and TNF-α may contribute to the growth and to the local aggressiveness of cutaneous melanoma. It opens the hypothesis of a direct oncogenic role of subcutaneous adipose tissue and adipokines in the tumorigenesis of melanoma.     

Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue

Epicardial adipose tissue (EAT) expresses lower levels of adiponectin in patients with CAD and higher levels of inflammatory mediators such as IL-6 and leptin than subcutaneous adipose tissue. This showed one important role of EAT in coronary artery disease. However, the relationship of EAT adiponectin and IL-6 levels to the extension of coronary artery disease has not hitherto been determined. We sought to determine whether the levels of adiponectin and interleukin-6 (IL-6) mRNA in epicardial adipose tissue are associated with the extension of coronary artery disease (CAD). Methods: Angiographic and hormones expression were evaluated from epicardial and subcutaneous adipose tissue. 92 patients (58 CAD, 34 non-CAD) who underwent cardiac surgery. Adiponectin and IL-6 mRNA levels were measured by real time RT-PCR in epicardial and subcutaneous adipose tissue (SAT) following angiographic evaluation of their coronary arteries. Results: We found that epicardial adipose tissue of CAD expressed lower levels of adiponectin mRNA and higher levels of IL-6 mRNA than that of non-CAD patients. As the number of injured arteries rose, adiponectin mRNA levels decreased (r = −0.402, p < 0.001) and IL-6 mRNA increased (r = 0.514, p < 0.001) in epicardial adipose tissue. Conclusions: The extension of CAD is significantly associated with the expression of adiponectin and IL-6 mRNA in EAT. These findings suggest that low adiponectin and high IL-6 expression by EAT may contribute to CAD extension.     

Exercise-induced lipid mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight men

Involvement of sympathetic nervous system and natriuretic peptides in the control of exercise-induced lipid mobilization was compared in overweight and lean men. Lipid mobilization was determined using local microdialysis during exercise. Subjects performed 35-min exercise bouts at 60% of their maximal oxygen consumption under placebo or after oral tertatolol [a beta-adrenergic receptor (AR) antagonist]. Under placebo, exercise increased dialysate glycerol concentration (DGC) in both groups. Phentolamine (alpha-AR antagonist) potentiated exercise-induced lipolysis in overweight but not in lean subjects; the alpha(2)-antilipolytic effect was only functional in overweight men. After tertatolol administration, the DGC increased similarly during exercise no matter which was used probe in both groups. Compared with the control probe under placebo, lipolysis was reduced in lean but not in overweight men treated with the beta-AR blocker. Tertatolol reduced plasma nonesterified fatty acids and insulin concentration in both groups at rest. Under placebo or tertatolol, the exercise-induced changes in plasma nonesterified fatty acids, glycerol, and insulin concentrations were similar in both groups. Exercise promoted a higher increase in catecholamine and ANP plasma levels after tertatolol administration. In conclusion, the major finding of our study is that in overweight men, in addition to an increased alpha(2)-antilipolytic effect, the lipid mobilization in subcutaneous adipose tissue that persists during exercise under beta-blockade is not dependent on catecholamine action. On the basis of correlation findings, it seems to be related to a concomitant exercise-induced rise in plasma ANP when exercise is performed under tertatolol intake and a decrease in plasma insulin.     

Interleukin-6 produced in subcutaneous adipose tissue is linked to blood pressure control in septic patients

Cytokines are inflammatory mediators of major relevance during sepsis. Recent evidence shows that adipose tissue can produce many distinct cytokines under physiological and pathological conditions, but the role of cytokines produced in adipose tissue was not addressed in sepsis. In the present study the open-flow microperfusion (OFM) technique was used to investigate whether the cytokines produced in subcutaneous adipose tissue (SAT) of patients with severe sepsis correlate with clinical variables. Interstitial fluid effluent samples were collected using an OFM catheter inserted in the abdominal SAT of nine patients with severe sepsis. Blood samples were withdrawn concomitantly and interleukin-1beta (IL-1beta), IL-8, IL-6 and tumor necrosis factor alpha (TNF-alpha) were measured both in SAT effluent and serum samples. Different time profiles were registered for each cytokine. IL-1beta increased in a time-dependent manner, indicating a localized response against the catheter insertion. Interleukin-1beta, 6 and 8 were higher in SAT than in serum suggesting they were locally produced. Diastolic blood pressure (DBP) negatively correlated with IL-1beta, IL-6 and IL-8 in SAT indicating a possible interaction between adipose tissue inflammation and vascular tone regulation. A multiple regression analysis disclosed that mean DBP was significantly related to IL-6 concentrations in SAT (B = −43.9; R-square = 0.82; P = 0.002).     

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.