Clinical and metabolic characterization of obese subjects without non-alcoholic fatty liver: A targeted metabolomics approach.

INTRODUCTION: As a small proportion of obese individuals do not develop metabolic complications and non-alcoholic fatty liver disease (NAFLD), this study aimed to provide a comprehensive clinical, metabolic and genetic description of obese subjects with healthy livers. METHODS: A total of 183 subjects were stratified, according to BMI, presence of metabolic syndrome, biochemical liver tests and hepatic steatosis on ultrasound, into: (i) lean controls (n = 69); (ii) obese healthy (n = 50); and (iii)obese NAFLD (n = 62) groups. Detailed clinical, genetic and metabolic evaluations were then performed. RESULTS: Obese healthy subjects did not differ in glucose parameters from lean controls, and had a lower rate of minor TM6SF2 gene variants compared with obese NAFLD (2/49 vs. 11/60, respectively; P = 0.035) and lean controls (13/64; P = 0.035), but significantly higher leptin concentrations than lean controls (P < 0.001); they also higher adiponectin concentrations (P < 0.001), and lower TNF-α and IL-6 concentrations (P = 0.01 and P < 0.001, respectively), than obese NAFLD subjects. Also, metabolomic studies identified ether- and ester-containing phospholipids [PC ae C44:6, PC ae C42:5, PC aa C40:4; P < 0.001, corrected by the false discovery rate (FDR) method] and found that the amino-acids lysine, glycine and isoleucine (FDR < 0.001) differed between the two obese groups, but not between lean controls and obese healthy subjects. CONCLUSION: Obese people with healthy livers are characterized by intact glucose homoeostasis, lower pro-inflammatory cytokine levels, and higher adiponectin and leptin concentrations compared with obese people with NAFLD. In addition, the major allele of TM6SF2, a set of phosphatidylcholines and several amino acids are associated with healthy livers in obesity.

Gender- and site-specific differences of colorectal neoplasia relate to vitamin D.

BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.

Salzburg Skiing for the Elderly Study: changes in cardiovascular risk factors through skiing in the elderly.

Numerous studies have shown that treatment of the modifiable cardiovascular risk factors (CVRF) results in a decreased risk to suffer from stroke or myocardial infarction. Despite the fact that exercise training is a potent treatment choice for CVRF, this is the first randomized study to assess the effects of alpine skiing on CVRF in elderly skiers. Subjects (n=42) were randomized into an intervention group (IG; n=22; 12 males/10 females; age: 66.6 ± 2.1 years) completing 12 weeks of guided skiing or a control group (CG; n=20; 10 males/10 females; age: 67.3 ± 4.4 years). CVRF were assessed before and after the intervention period. No cardiovascular event occurred within a total of 795.1 h of skiing. A significant increase in exercise capacity in IG (ΔVO(2 max) : +2.0 mL/kg/min, P=0.005) but not in CG (ΔVO(2 max) : -0.1 mL/kg/min, P=0.858; IG vs CG: P=0.008) as well as a decrease in body fat mass [IG: -2.3%, P<0.0001; CG: ± 0.0%, P=0.866; IG vs CG: P<0.0001] was achieved. Blood pressure, blood lipids, heart rate and everyday physical activity remained essentially unchanged. Alpine skiing in the elderly is safe with respect to cardiovascular events, and improves some, but not all CVRF.

Glucose homeostasis and cardiovascular disease biomarkers in older alpine skiers.

Alpine skiing and ski training involves elements of static and dynamic training, and may therefore improve insulin sensitivity. Healthy men and women who where beginners/intermediate level of alpine skiing, were studied before (Pre) and immediately after (Post) 12 weeks of alpine ski training. After an additional 8 weeks a third test (retention study, Ret) was performed. The subjects were randomized into an intervention group (IG, n=22, age=66.6 ± 0.4 years) or a control group (CG, n=20, age=67.0 ± 1.0 years). Plasma glucose decreased (P<0.05) in CG, but increased (P<0.05) again at Ret, while a continued decrease was seen in IG (Ret vs Post, P<0.05). Plasma insulin decreased (P<0.05) with training in IG, while no effect was seen in CG. HOMA2 index for insulin resistance decreased (P<0.05) from 0.80 ± 0.08 to 0.71 ± 0.09 in IG. The value at Ret (0.57 ± 0.08) tended (P=0.067) to be different from Post. In CG the corresponding values were 0.84 ± 0.09, 0.81 ± 0.12 and 0.70 ± 0.09, respectively. Total cholesterol and LDL decreased in both IC and CG, a result, interpreted as seasonal variation. Biomarkers for endothelial function and low-grade inflammation were not elevated and similar in IG and CG, and did not change. Alpine ski training improves glucose homeostasis and insulin sensitivity in healthy, elderly individuals.

Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of insulin resistance (IR), and IR is associated with an increased risk of colorectal carcinoma (CRC). Increased echogenicity suggesting NAFLD is a frequent incidental finding on ultrasound examination. We aimed to systematically evaluate whether NAFLD is an independent risk factor for colonic neoplasia. PATIENTS AND METHODS: One thousand two hundred and eleven patients (603 males, 60.6 ± 9.6 years; 608 females, 61.1 ± 10.3 years) who underwent screening colonoscopy according to national screening recommendations for CRC were evaluated in a cross-sectional study. Colorectal adenomas were classified as tubular adenoma, advanced adenoma (villous features, size ≥ 1 cm or high-grade dysplasia) or carcinoma. NAFLD was diagnosed by increased echogenicity on ultrasound examination after serological exclusion of infectious, immunological, hereditary or alcoholic aetiology. RESULTS: Nonalcoholic fatty liver disease was diagnosed in 367 (60.8%) males and in 265 (43.5%) females. The total rate of adenomas was increased in subjects with NAFLD (243/367 vs. 107/236 in males, P = 0.010; 94/265 vs. 78/343 in females; P = 0.014). In particular, more tubular adenomas (127/367 vs. 56/236; P = 0.006), adenomas of the rectum (40/367 vs. 8/236; P = 0.004) and more cancers (6/367 vs. 1/236; P < 0.001) were observed in males with NAFLD. In females with NAFLD, more tubular adenomas (59/265 vs. 48/343; P = 0.011) and adenomas of the proximal colon (51/265 vs. 40/343; P = 0.041) were observed. Multivariate regression analyses demonstrated an independent association of colorectal adenomas with hepatic steatosis after adjustment for age, sex, body mass index and glucose intolerance (OR 1.47; 95% CI 1.079-2.003; P = 0.015). CONCLUSION: Patients with NAFLD undergoing screening colonoscopy reveal significantly more CRC precursor lesions and early CRC compared with subjects without NAFLD. This elevated risk is independent from other manifestations of IR. These findings suggest that detecting fatty liver on ultrasound should heighten the awareness for referral to screening colonoscopy.

Aberrant hepatic TRIB3 gene expression in insulin-resistant obese humans.

AIMS/HYPOTHESIS: The pseudokinase tribbles homologue 3 (Drosophila) (TRIB3) negatively interferes with insulin-mediated phosphorylation and activation of v-akt murine thymoma viral oncogene homologue 1 (AKT1, also known as protein kinase B). Animal studies have shown that Trib3 expression was higher in the fasting state and in animal models of diabetes, promoting hyperglycaemia presumably by increasing glucose production in the liver. Less is known about the role of TRIB3 in insulin resistance in humans, although a gain-of-function mutation associated with abnormalities related to insulin resistance has been described in TRIB3. METHODS: We determined hepatic mRNA expression of TRIB3 and selected genes encoding enzymes, transcription factors and coactivators involved in glucose homeostasis. We also determined biochemical variables of intermediary metabolism in obese patients with varying degrees of insulin resistance. RESULTS: In our study population hepatic TRIB3 mRNA expression was associated with surrogate markers of insulin resistance. TRIB3 expression was significantly increased in a subgroup with high HOMA of insulin resistance (HOMA-IR) compared with a low HOMA-IR group (p = 0.0033). TRIB3 transcript levels were correlated with PEPCK (also known as PCK2) mRNA expression (p = 0.0014) and mRNA expression of PPARGC1A (p = 0.0020), PPARGC1B (p < 0.0001), USF1 (p = 0.0017), FOXO1 (p = 0.0003) and SREBP-1c (also known as SREBF1; p = 0.0360). Furthermore ligands of peroxisome proliferator-activated receptor alpha/retinoid X receptor and overexpression of its coactivator PPARGC1A as well as overexpression of SREBP-1c and its coactivator PPARGC1B increased TRIB3 promoter activity in HepG2 cells. CONCLUSIONS/INTERPRETATION: We have found evidence for a role of aberrant hepatic TRIB3 transcript levels in insulin resistance in obese humans and identified potential transcriptional pathways involved in regulation of TRIB3 gene expression in the liver.

Hepatic adiponectin receptors (ADIPOR) 1 and 2 mRNA and their relation to insulin resistance in obese humans.

OBJECTIVE: Adiponectin signalling attenuates insulin resistance (IR) and steatosis hepatis in animal models. As adiponectin receptor (ADIPOR)1 and ADIPOR2 are critical components in the adiponectin signalling cascade, we studied hepatic ADIPOR1/2 mRNA levels in humans and their relation to IR. DESIGN: We determined metabolic risk factors and levels of hepatic mRNA transcribed from ADIPOR1, ADIPOR2 and FOXO1, a putative up-stream regulator, in 43 and 34 obese subjects with low and high homeostasis model assessment-IR, respectively. RESULTS: Plasma adiponectin and metabolic risk factors showed associations with IR as expected. Both hepatic ADIPOR1 and ADIPOR2 mRNA expression levels were higher in insulin-resistant subjects (P<0.0035). ADIPOR1 mRNA correlated with FOXO1 mRNA in obese insulin resistant (P=0.0034), but not insulin-sensitive subjects, while no correlations of ADIPOR2 with FOXO1 mRNA were noted. FOXO1 enhanced transcription from the ADIPOR1, but not the ADIPOR2 promoter in HepG2 cells. CONCLUSION: Increased hepatic ADIPOR1 and ADIPOR2 mRNA in insulin-resistant obese subjects may, at least in part, reflect a compensatory mechanism for reduced plasma adiponectin. FOXO1 may contribute to enhanced ADIPOR1, but not ADIPOR2 transcription in IR.

Iron stores, liver transaminase levels and metabolic risk in healthy teenagers.

BACKGROUND: Iron overload may contribute to the pathogenesis of insulin resistance. We aimed to investigate the relationship among iron stores, liver transaminases and components of the metabolic syndrome in healthy teenagers in a cross-sectional study. MATERIAL AND METHODS: We determined body mass index (BMI), waist-to-hip-ratio (WHR), blood pressure, liver ultrasound, serum lipids, insulin, fasting glucose, liver transaminase levels, hsCRP, iron parameters in 325 of 341 (95.3%) students (234 men, 16.7 +/- 1.7 years; 91 women, 16.5 +/- 1.7 years) of one single high school. Male and female study participants were allocated to increasing quartiles of body iron stores as assessed by sTfr/ferritin and alanine aminotranspeptidase (ALT) levels, and the distribution of cardiometabolic risk factors along quartiles was analysed. Regression analysis was performed to confirm the independent relationship between parameters. RESULTS: In male students, BMI, WHR, systolic and diastolic blood pressure, serum triglyceride levels and hsCRP were higher in the top sTfR/ferritin and ALT quartiles compared with the lowest quartiles (P < 0.01 for all parameters). In female students, sTfR/ferritin were not associated with antropomorphic cardiometabolic risk factors but with insulin resistance (HOMA-IR, P = 0.046). Moreover, ALT levels were independently related to BMI, waist and hip circumference, systolic blood pressure, serum triglyceride and insulin concentrations (P < 0.05 for all parameters) in female students. CONCLUSION: These results provide evidence for linkage among body iron stores, transaminase activity and the prevalence of cardiometabolic risk factors in apparently healthy, non-obese adolescents even within the range of normal laboratory and anthropomorphic values and suggest that iron stores should be investigated as a potentially modifiable risk factor in healthy teenagers.

Determinants of plasma apolipoprotein A-V and APOA5 gene transcripts in humans.

OBJECTIVE: Apolipoprotein A-V (apoAV) contributes to the regulation of triglyceride metabolism, which plays a role in the pathogenesis of atherosclerotic diseases. We therefore ascertained determinants of hepatic APOA5 transcript and apoAV plasma levels in humans. DESIGN: We determined influences of anthropometric variables, biochemical factors related to lipid and glucose metabolism, hepatic mRNA levels transcribed from the APOA1/C3/A4/A5 cluster and transcription factor genes implicated in the regulation of APOA5 as well as common single nucleotide polymorphisms (SNPs) at the APOA5 locus on APOA5 expression in 89 obese patients and 22 non-obese controls. RESULTS: Mean, age and sex adjusted, hepatic APOA5 mRNA or apoAV plasma levels did not differ by obesity status, homoeostasis model assessment insulin resistance or inflammatory markers. In multivariate regression models, the c56C > G SNP, plasma apoCIII, plasma nonesterified fatty acids, hepatic APOA5 transcripts, sex and a weak association with obesity status explained 61% of the variance in apoAV plasma levels. Hepatic transcript levels of carnitine palmitoyltransferase 1 (CPT1A1) and peroxisome proliferator-activated receptor alpha (PPARA), plasma nonesterified fatty acids and the c56C > G SNP explained 48% of the variance in hepatic APOA5 transcript levels. CONCLUSION: Apolipoprotein A-V plasma levels are independently associated with plasma free fatty acid and hepatic APOA5 mRNA levels. Associations of APOA5 transcripts with PPARA and CPT1A1 transcripts suggest that APOA5 expression is intimately linked to hepatic lipid metabolism.

Contribution of anti-cyclic citrullinated peptide antibody and rheumatoid factor to the diagnosis of arthropathy in haemochromatosis.

OBJECTIVE: To investigate the prevalence of antibodies to cyclic citrullinated peptide (anti-CCP) and rheumatoid factor in patients with hereditary haemochromatosis (HHC) and to evaluate their diagnostic reliability in distinguishing HHC-associated arthropathy from rheumatoid arthritis. METHODS: Anti-CCP antibodies and rheumatoid factor levels were determined by ELISA in sera from 87 patients with HHC homozygous for the C282Y mutation of the HFE gene, 31 patients with rheumatoid arthritis and 162 healthy controls. RESULTS: Of the 87 patients with HHC, 32 (36.8%) had joint involvement. Anti-CCP antibodies were detected in only 1 patient (1.1%) with HHC, who had no joint disease, and in (1.2%) healthy controls. In total, 18 (58.1%) patients with rheumatoid arthritis displayed anti-CCP reactivity (p<0.001). Rheumatoid factor was detected in 10 (11.5%) patients with HHC compared with 7 (4.3%) healthy control subjects (p = 0.03) and 21 of 31 (65.6%) patients with rheumatoid arthritis. CONCLUSIONS: Testing for anti-CCP antibodies discriminates HHC arthropathy from rheumatoid arthritis, as these patients were consistently anti-CCP negative. Thus, HHC arthropathy should be considered in the differential diagnosis of CCP-negative arthritis.

The SREBF-1 locus is associated with type 2 diabetes and plasma adiponectin levels in a middle-aged Austrian population.

CONTEXT: The sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription factor involved in the regulation of lipid and glucose metabolism and has been implicated in the pathophysiology of type 2 diabetes mellitus (T2DM). OBJECTIVE: We aimed to confirm associations of the SREBF-1 gene with T2DM in an Austrian population and to study possible associations with diabetes-related quantitative traits. DESIGN, SETTINGS AND PARTICIPANTS: We genotyped a diabetic cohort (n=446) along with a control group (n=1524) for a common C/G variation that is located in exon 18c (rs2297508) and has been associated with obesity and T2DM in French populations. MAIN OUTCOME MEASURES: Body mass index (BMI), indices of insulin sensitivity and beta-cell function, plasma adiponectin, T2DM and single-nucleotide polymorphism rs2297508. RESULTS: Genotype distributions associated with rs2297508 differed by T2DM status (P=0.0045), but not by BMI. The variant G allele was associated with a modest, but significant, increase in the prevalence of T2DM after adjustment for age, sex and BMI (G/G: odds ratios (OR) (95% confidence intervals)=1.45 (0.99-2.11) and G/C: OR=1.37 (1.04-1.81)). In a cross-sectional population of non-diabetic subjects, associations of rs2297508 genotypes with plasma adiponectin levels adjusted for age, sex and BMI (P=0.0017) were observed in that the risk G/G genotype displayed the lowest adiponectin levels. CONCLUSIONS: We observed associations of rs2297508 with T2DM prevalence and plasma adiponectin. SREBP-1c has been implicated in the regulation of adiponectin gene expression. Our results therefore raise the possibility that sequence variations at the SREBF-1 gene locus might contribute to T2DM risk, at least in part, by altering circulating adiponectin levels.

PGC-1alpha: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes.

Data derived from several recent studies implicate peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) in the pathogenesis of type 2 diabetes. Lacking DNA binding activity itself, PGC-1alpha is a potent, versatile regulator of gene expression that co-ordinates the activation and repression of transcription via protein-protein interactions with specific, as well as more general, factors contained within the basal transcriptional machinery. PGC-1alpha is suggested to play a pivotal role in the control of genetic pathways that result in homeostatic glucose utilisation in liver and muscle, beta cell insulin secretion and mitochondrial biogenesis. This review focuses on the role of PGC-1alpha in glucose metabolism and considers how PGC-1alpha links cellular glucose metabolism, insulin sensitivity and mitochondrial function, and why defects in PGC-1alpha expression and regulation may contribute to the pathophysiology of type 2 diabetes in humans.

Apolipoprotein AV does not contribute to hypertriglyceridaemia or triglyceride lowering by dietary fish oil and rosiglitazone in obese Zucker rats.

AIMS/HYPOTHESIS: Apolipoprotein AV (apoAV) is a recently discovered apolipoprotein with a triglyceride-lowering effect in genetically modified mice. Transcription of the human gene encoding apoAV (APOA5) is suppressed by insulin and stimulated by fibrates. Our goal was to study the expression of Apoa5, in comparison with Apoa4 and Apoc3, in hypertriglyceridaemic, obese and insulin-resistant Zucker rats receiving the insulin sensitiser rosiglitazone and/or a fish oil diet to lower triglycerides. METHODS: Hepatic Apoa5, Apoa4 and Apo3 mRNA and liver and plasma apoAV were measured in lean and obese Zucker rats receiving rosiglitazone while on a coconut oil or fish oil diet. RESULTS: Basal hepatic Apoa5 expression was similar in obese and lean Zucker rats. Unexpectedly, obese Zucker rats tended to have higher plasma apoAV levels despite their hypertriglyceridaemic state. Both rosiglitazone and the fish oil diet significantly increased Apoa5 mRNA, by about 70%, but tended to lower liver and plasma apoAV. Rosiglitazone had no effect on Apoa5 mRNA in cultured rat hepatocytes. No intact PPAR (peroxisome proliferator-activated receptor) response element was identified in the rat Apoa5 promoter. CONCLUSIONS/INTERPRETATION: Our data indicate that apoAV does not contribute to the hypertriglyceridaemia of obese Zucker rats or to the hypolipidaemic effect of rosiglitazone or a fish oil diet. The divergent changes of Apoa5 mRNA and apoAV levels suggest co- or post-translational regulation. The increase in Apoa5 mRNA induced by rosiglitazone is not directly mediated by peroxisome proliferator-activated receptor gamma.

Associations of the UCP2 gene locus with asymptomatic carotid atherosclerosis in middle-aged women.

OBJECTIVE: Reactive oxygen species (ROS) contribute to atherogenesis. Uncoupling protein 2 (UCP2) reduces mitochondrial ROS generation and protects against the disease in animal models. A common -866G/A promoter polymorphism that has been associated with obesity and beta-cell function may also affect UCP2 gene expression in cells of the arterial wall. METHODS AND RESULTS: Genotype distributions of the -866G/A and of a 45nt-del/ins polymorphism in the 3'-untranslated region of the UCP2 gene were determined in 1334 participants of the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR). We observed a modest association of the -866G/A promoter polymorphism and 2-loci haplotypes with asymptomatic carotid atherosclerosis in female study participants. Functional studies revealed increased expression of the -866G wild-type allele in human umbilical vein endothelial cells and differentiated THP-1 cells. Electrophoretic mobility shift assay studies and antibody-interference assays performed with nuclear extracts of various cell lines showed binding of cell-type specific protein complexes to the region encompassing the -866 site and suggested involvement of hypoxia inducible factor 1alpha in the regulation of UCP2 gene expression in endothelial cells and macrophages. CONCLUSIONS: Our results suggest a role of UCP2 in atherogenesis as originally proposed from studies in animal and cell culture models.

Decrease of plasma apolipoprotein A-IV during weight reduction in obese adolescents on a low fat diet.

OBJECTIVE: Apolipoprotein (apo) A-IV is an antiatherogenic apolipoprotein, which may be involved in the regulation of food intake. Plasma apoA-IV is elevated in human obesity and apoA-IV polymorphisms have been associated with the extent of obesity. Our aim was to determine the effects of weight loss on plasma apo-IV in obese adolescents and to examine the relation of apoA-IV with the degree of obesity. DESIGN: Longitudinal intervention study of a low fat hypocaloric diet conducted in a dietary camp. SUBJECTS: Two groups of obese adolescents (n=47 and n=29), age: 12.7+/-1.7 and 11.7+/-2.6 y, relative body mass index (RBMI): 168+/-24 and 175+/-34%, respectively. MEASUREMENTS: Plasma total apoA-IV, apoA-I, apoB, plasma distribution of apoA-IV, leptin, lipids, and lipoproteins before and after 3 weeks of weight reduction. RESULTS: Plasma apoA-IV decreased from 11.5+/-4.1 mg/dl before to 6.7+/-2.2 mg/dl after weight reduction in the first group (P<0.001) and to a similar extent in the second group. The relative amount of lipid-free apoA-IV and apoA-IV associated with apoA-I increased slightly, whereas apoA-IV associated with lipoproteins devoid of apoA-I decreased. ApoA-IV levels before and after weight reduction and the changes in plasma apoA-IV did not independently correlate with RBMI, weight loss, or plasma leptin. CONCLUSION: Plasma apoA-IV decreases markedly in overweight adolescents undergoing short-term weight reduction. The decrease is not directly related to the degree of weight loss and the mechanisms underlying this reduction remain to be clarified.

Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse. METHODS AND RESULTS: After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C. CONCLUSIONS: Optimal LDL-C values are <100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men.

A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans.

Obesity is the most common nutritional disorder in Western society. Uncoupling protein-2 (UCP2) is a recently identified member of the mitochondrial transporter superfamily that is expressed in many tissues, including adipose tissue. Like its close relatives UCP1 and UCP3, UCP2 uncouples proton entry in the mitochondrial matrix from ATP synthesis and is therefore a candidate gene for obesity. We show here that a common G/A polymorphism in the UCP2 promoter region is associated with enhanced adipose tissue mRNA expression in vivo and results in increased transcription of a reporter gene in the human adipocyte cell line PAZ-6. In analyzing 340 obese and 256 never-obese middle-aged subjects, we found a modest but significant reduction in obesity prevalence associated with the less-common allele. We confirmed this association in a population-based sample of 791 middle-aged subjects from the same geographic area. Despite its modest effect, but because of its high frequency (approximately 63%), the more-common risk allele conferred a relatively large population-attributable risk accounting for 15% of the obesity in the population studied.

Metabolic and lifestyle determinants of postprandial lipemia differ from those of fasting triglycerides: The Atherosclerosis Risk In Communities (ARIC) study.

Despite the reported association of lipoprotein responses to a fatty meal with atherosclerosis, little is known about the determinants of these responses. Plasma triglyceride, retinyl palmitate, and apolipoprotein B-48 responses to a standardized fatty meal containing a vitamin A marker were measured in 602 Atherosclerosis Risk in Communities (ARIC) study participants. To focus on postprandial responses specifically, which have been reported to be related to atherosclerosis independently of fasting triglycerides, analyses for determinants of postprandial responses were adjusted for fasting triglycerides. Major determinants of fasting triglycerides, namely, diabetes, obesity, other factors related to insulin resistance, and male sex, were not independently associated with postprandial responses. Fasting triglycerides were the strongest predictor of postprandial lipids, but independent of triglycerides, the predictors of postprandial responses were smoking, diet, creatinine, and alcohol. Smokers had substantially increased retinyl palmitate and apolipoprotein B-48 responses, indicators of chylomicrons and their remnants. Persons who consume more calories or omega3 fatty acids had reduced chylomicron responses. Triglyceride responses were associated positively with serum creatinine levels and negatively with moderate alcohol consumption. Thus, determinants of fasting and postprandial lipids differ. The independent atherogenic influence of postprandial lipids may relate more to smoking and diet than to obesity and insulin resistance.

UCP3 gene expression does not correlate with muscle oxidation rates in troglitazone-treated Zucker fatty rats.

Uncoupling protein-3 (UCP3), a mitochondrial carrier protein predominantly expressed in muscle, has been suggested to release stored energy as heat. The insulin-sensitizing thiazolidinediones enhance glucose disposal in skeletal muscle and have been reported to increase the expression of uncoupling proteins in various experimental systems. We therefore studied the effect of troglitazone treatment on UCP3 gene expression in muscles from lean and obese Zucker rats. In comparison with obese littermates, basal UCP3 mRNA levels in lean Zucker rats tended to be higher in white and red gastrocnemius muscles, but were lower in soleus (P<0.001) muscle and heart (P<0.01). In lean rats, troglitazone significantly increased UCP3 gene expression in white and red gastrocnemius and heart muscles (all P<0.01). In contrast, the drug reduced UCP3 mRNA expression in red gastrocnemius and soleus muscles of obese littermates (all P<0.001). The troglitazone-dependent decrease in UCP3 gene expression was accompanied by an increased weight gain in obese rats, while no such effect was observed in lean rats. In obese rats, improvement of insulin resistance by troglitazone was associated with increased rates of basal and insulin-stimulated CO(2) production from glucose measured in soleus muscle. These studies demonstrate that effects of troglitazone on UCP3 gene expression depend on the phenotype of Zucker rats and that troglitazone-induced metabolic improvements are not related to increased uncoupling resulting from upregulation of UCP3 mRNA expression in muscle.