Christoph H. Saely

Brown versus White Adipose Tissue: A Mini-Review

Background: Brown adipose tissue (BAT) is abundant in small mammals and in newborns and helps them to survive cold temperatures. In adults, it had long been considered to be absent or at least of no relevance. Recent investigations, however, have fuelled interest in adult BAT. Objective: We aimed at (1) summarizing structural and physiological characteristics of BAT versus white adipose tissue (WAT); (2) discussing the development of the two adipose tissue types; (3) reviewing the data available from human studies on BAT, and (4) discussing the impact of aging. Methods: We summarize recent descriptions of BAT and WAT based on the original literature and reviews in the field, with emphasis on human BAT. Results: WAT and BAT have essentially antagonistic functions: WAT stores excess energy as triglycerides and BAT is specialized in the dissipation of energy through the production of heat. Considerable amounts of BAT are present in a substantial proportion of adult humans and relatively high quantities of BAT are associated with lower body weight. With increasing age, BAT decreases and body weight increases. Conclusions: Although the available cross-sectional data do not allow definite conclusions to be drawn concerning a causal relationship between loss of BAT and increasing body weight with advancing age or obesity-related metabolic disorders of older age, stimulation of BAT appears to be an attractive novel candidate target for the treatment of age-related obesity.

Bile Acid Metabolites in Serum: Intraindividual Variation and Associations with Coronary Heart Disease, Metabolic Syndrome and Diabetes Mellitus

Bile acids (BAs) regulate glucose and lipid metabolism. In longitudinal and case-control-studies, we investigated the diurnal variation of serum concentrations of the 15 major BAs as well as the biosynthetic precursor 7α-hydroxy-4-cholesten-3-one (C4) and their associations, respectively, with coronary artery disease (CAD), diabetes mellitus type 2 (T2DM), and non-diabetic metabolic syndrome (MetS). In hourly taken blood samples of four healthy probands, the intraindividual 24 h variation of C4, conjugated and unconjugated BAs ranged from 42% to 72%, from 23% to 91%, and from 49% to 90%, respectively. Conjugated BA concentrations mainly increased following food intake. Serum levels of C4 and unconjugated BAs changed with daytime with maxima varying interindividually between 20h00 and 1h00 and between 3h00 and 8h00, respectively. Comparisons of data from 75 CAD patients with 75 CAD-free controls revealed no statistically significant association of CAD with BAs or C4. Comparisons of data from 50 controls free of T2DM or MetS, 50 MetS patients, and 50 T2DM patients revealed significantly increased fasting serum levels of C4 in patients with MetS and T2DM. Multiple regression analysis revealed body mass index (BMI) and plasma levels of triglycerides (TG) as independent determinants of C4 levels. Upon multivariate and principle component analyses the association of C4 with T2DM and/or MetS was not independent of or superior to the canonical MetS components. In conclusion, despite large intra- and interindividual variation, serum levels of C4,are significantly increased in patients with MetS and T2DM but confounded with BMI and TG.

Lipoprotein(a), type 2 diabetes and vascular risk in coronary patients

Background  Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor in the general population. However, prospective data on the vascular risk conferred by Lp(a) in patients with diabetes mellitus are scarce and controversial. It is not known whether the diabetic state affects the association of Lp(a) with vascular events among coronary patients.

Single nucleotide polymorphisms of TCF7L2 are linked to diabetic coronary atherosclerosis.

Background Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients. Methodology/Principal Findings We genotyped TCF7L2 variants rs7903146, rs12255372, and rs11196205 in a cross-sectional study including 1,650 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable CAD. Significant CAD was diagnosed in the presence of coronary stenoses ≥50%. Variant rs7903146 in the total study cohort was significantly associated with significant CAD (adjusted additive OR = 1.29 [1.09–1.53]; p = 0.003). This association was strong and significant in T2DM patients (n = 393; OR = 1.91 [1.32–2.75]; p = 0.001) but not in non-diabetic subjects (OR = 1.09 [0.90–1.33]; p = 0.370). The interaction risk allele by T2DM was significant (pinteraction = 0.002), indicating a significantly stronger impact of the polymorphism on CAD in T2DM patients than in non-diabetic subjects. TCF7L2 polymorphisms rs12255372 and rs11196205 were also significantly associated with CAD in diabetic patients (adjusted additive OR = 1.90 [1.31–2.74]; p = 0.001 and OR = 1.75 [1.22–2.50]; p = 0.002, respectively). Further, haplotype analysis demonstrated that haplotypes including the rare alleles of all investigated variants were significantly associated with CAD in the whole cohort as well as in diabetic subjects (OR = 1.22 [1.04–1.43]; p = 0.013 and OR = 1.67 [1.19–2.22]; p = 0.003, respectively). Conclusions/Significance These results suggest that TCF7L2 variants rs7903146 rs12255372, and rs11196205 are significantly associated with angiographically diagnosed CAD, specifically in patients with T2DM. TCF7L2 therefore appears as a genetic link between diabetes and atherosclerosis.

Identification of Hypoxia-Induced Genes in Human SGBS Adipocytes by Microarray Analysis

Hypoxia in adipose tissue is suggested to be involved in the development of a chronic mild inflammation, which in obesity can further lead to insulin resistance. The effect of hypoxia on gene expression in adipocytes appears to play a central role in this inflammatory response observed in obesity. However, the global impact of hypoxia on transcriptional changes in human adipocytes is unclear. Therefore, we compared gene expression profiles of human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes under normoxic or hypoxic conditions to detect hypoxia-responsive genes in adipocytes by using whole human genome microarrays. Microarray analysis showed more than 500 significantly differentially regulated mRNAs after incubation of the cells under low oxygen levels. To gain further insight into the biological processes, hypoxia-regulated genes after 16 hours of hypoxia were classified according to their function. We identified an enrichment of genes involved in important biological processes such as glycolysis, response to hypoxia, regulation of cellular component movement, response to nutrient levels, regulation of cell migration, and transcription regulator activity. Real-time PCR confirmed eight genes to be consistently upregulated in response to 3, 6 and 16 hours of hypoxia. For adipocytes the hypoxia-induced regulation of these genes is shown here for the first time. Moreover in six of these eight genes we identified HIF response elements in the proximal promoters, specific for the HIF transcription factor family members HIF1A and HIF2A. In the present study, we demonstrated that hypoxia has an extensive effect on gene expression of SGBS adipocytes. In addition, the identified hypoxia-regulated genes are likely involved in the regulation of obesity, the incidence of type 2 diabetes, and the metabolic syndrome.

The -11377 C>G promoter variant of the adiponectin gene, prevalence of coronary atherosclerosis, and incidence of vascular events in men.

No prospective data demonstrating an association between the –11377 C>G adiponectin gene promoter variant and cardiovascular risk are available.We therefore prospectively evaluated the cardiovascular risk associated with adiponectin gene single nucleotide polmorphisms (SNPs) including SNP –11377 in a consecutive series of men undergoing coronary angiography. We recorded vascular events over four years in 402 men undergoing coronary angiography for the evaluation of coronary artery disease. No significant associations of SNPs +276 G>T and +45 T>G with serum adiponectin,with significant coronary stenoses >50%, or with vascular events were observed. However, for SNP –11377 C>G, serum adiponectin levels significantly decreased (ptrend = 0.003), and the prevalence of significant coronary stenoses significantly increased from the CC over the GC to the GG genotype (ptrend = 0.004). Prospectively, the risk of vascular events significantly increased from the CC over the CG to the GG genotype of this SNP (adjusted hazard ratios 1.555 [0.957 – 2.525] and 2.309 [1.067 – 4.998],respectively;ptrend = 0.014).The –11377 C>G adiponectin gene promoter variant is i) associated with decreased serum adiponectin levels, ii) correlated with the presence of coronary atherosclerosis and iii) significantly predictive of vascular events among men undergoing coronary angiography.

Metabolic and anti-inflammatory benefits of eccentric endurance exercise – a pilot study

Background  Eccentric endurance exercise (e.g. hiking downwards) is less strenuous than concentric exercise (e.g. hiking upwards) but its potential to reduce cardiovascular risk is unknown.

Key role of postchallenge hyperglycemia for the presence and extent of coronary atherosclerosis: An angiographic study

BACKGROUND The associations between impaired glucose tolerance (IGT) and postchallenge diabetes with the presence and extent of angiographically characterized coronary atherosclerosis are unclear. MATERIALS AND METHODS We enrolled 1040 consecutive Caucasian patients undergoing coronary angiography for the evaluation of coronary artery disease (CAD). An oral 75-g glucose tolerance test was performed in patients without previously diagnosed diabetes. RESULTS From our patients, 394 had normal glucose tolerance (NGT), 190 impaired glucose tolerance (IGT), 90 isolated postchallenge diabetes (postchallenge glucose >or=200 mg/dl), and 366 type 2 diabetes previously established or newly diagnosed on the basis of fasting glucose (conventional diabetes). Coronary atherosclerosis was more frequent in patients with IGT, isolated postchallenge diabetes, or conventional diabetes when compared to NGT subjects (87.9, 95.6, 89.1 versus 80.7%; p=0.030, 0.001, 0.043, respectively). The prevalence of significant coronary stenoses >or=50%, compared to NGT subjects (57.4%), was similar in IGT patients (59.5%; p=0.628), but significantly higher in patients with isolated postchallenge diabetes (77.8%; p=0.001) or conventional diabetes (68.0%; p=0.002). Also the number of significant stenoses compared to NGT subjects was similar in IGT patients, but significantly higher in those with isolated postchallenge or conventional diabetes. These results were confirmed after multivariate adjustment. CONCLUSIONS Abnormal glucose tolerance is strongly and independently associated with angiographically characterized coronary atherosclerosis. In IGT, non-significant coronary atherosclerosis is more frequent than in NGT; the prevalence and number of significant stenoses increases when postchallenge diabetes evolves.

Significant impact of chromosomal locus 1p13.3 on serum LDL cholesterol and on angiographically characterized coronary atherosclerosis.

OBJECTIVES Recently, a significant impact of a new locus on chromosome 1p13.3 on serum LDL (low-density lipoprotein) cholesterol and clinical events of coronary artery disease (CAD) was described. Potential associations between variants on this locus and angiographically characterized coronary atherosclerosis are unknown. We therefore aimed at investigating the association of variants of locus 1p13.3 with coronary atherosclerosis. METHODS We performed genotyping of variants rs599839, rs646776, and rs4970834 on chromosome 1p13.3 in a large cohort of 1610 consecutive Caucasian patients undergoing coronary angiography, where lesions of 50% or more were classified as significant. RESULTS Compared to the homozygous common allele the rare alleles of variants rs599839, rs646776, and rs4970834 were significantly associated with decreased serum LDL cholesterol (132+/-40mg/dl vs. 125+/-36mg/dl, P=0.003, 132+/-40mg/dl vs. 124+/-36mg/dl, P<0.001, and 131+/-40mg/dl vs. 125+/-37mg/dl, P=0.005, respectively). Further, carriers of the rare alleles of variants rs599839 and rs646776 were at a significantly lower risk of significant coronary stenoses than subjects who were homozygous for the frequent alleles, with odds ratios (ORs) of 0.78 [0.63-0.96]; P=0.019 and 0.74 [0.60-0.91]; P=0.004, respectively. After multivariate adjustment including LDL cholesterol, the protective effect of the rare allele of variant rs646776, but not of variant rs599839, on CAD risk remained significant (OR=0.77 [0.61-0.98], P=0.034). CONCLUSIONS We conclude that chromosomal locus 1p13.3 is significantly associated with both, serum LDL cholesterol and coronary atherosclerotic lesions.

Factors predicting cardiovascular events in statin-treated diabetic and non-diabetic patients with coronary atherosclerosis

OBJECTIVE We aimed at identifying which lipid factors drive vascular risk in statin-treated patients with coronary artery disease (CAD). METHODS We recorded vascular events over 5.6 years in 491 consecutive statin-treated patients with angiographically proven stable CAD, covering 2750 patient-years. RESULTS In the total population, low high-density lipoprotein (HDL) cholesterol (standardized adjusted HR 0.73 [0.60-0.89]; p=0.001), low apolipoprotein A1 (0.77 [0.65-0.92]; p=0.003), a small low-density lipoprotein (LDL) particle diameter (0.76 [0.64-0.91]; p=0.002), and high triglycerides (1.20 [1.05-1.38]; p=0.007) predicted vascular events, but not total cholesterol, LDL cholesterol, or apolipoprotein B. Factor analysis in the lipid profiles of our patients revealed an HDL-related factor and an LDL-related factor. Concordant with the results for individual lipid parameters, the HDL-related factor (0.69 [0.58-0.83]; p<0.001) but not the LDL-related factor (p=0.455) predicted vascular events. Patients with type 2 diabetes (T2DM; n=116) were at a higher vascular risk than non-diabetic subjects (38.6% vs. 24.1%; p<0.001), and like in the total population the HDL-related factor (0.59 [0.44-0.77]; p<0.001) but not the LDL-related factor (p=0.591) predicted vascular risk in diabetic patients. CONCLUSIONS The pattern of low HDL cholesterol, low apolipoprotein A1, small LDL particles, and high triglycerides drives vascular risk in statin-treated coronary patients, particularly in those with T2DM.