Depot-specific differences in fatty acid composition and distinct associations with lipogenic gene expression in abdominal adipose tissue of obese women.

Cardiometabolic diseases are primarily linked to enlarged visceral adipose tissue (VAT). However, some data suggest heterogeneity within the subcutaneous adipose tissue (SAT) depot with potential metabolic differences between the superficial SAT (sSAT) and deep SAT (dSAT) compartments. We aimed to investigate the heterogeneity of these three depots with regard to fatty acid (FA) composition and gene expression. Adipose tissue biopsies were collected from 75 obese women undergoing laparoscopic gastric bypass surgery. FA composition and gene expression were determined with gas chromatography and quantitative real-time-PCR, respectively. Stearoyl CoA desaturase-1 (SCD-1) activity was estimated by product-to-precursor FA ratios. All polyunsaturated FAs (PUFA) with 20 carbons were consistently lower in VAT than either SAT depots, whereas essential PUFA (linoleic acid, 18:2n-6 and α-linolenic acid, 18:3n-3) were similar between all three depots. Lauric and palmitic acid were higher and lower in VAT, respectively. The SCD-1 product palmitoleic acid as well as estimated SCD-1 activity was higher in VAT than SAT. Overall, there was a distinct association pattern between lipid metabolizing genes and individual FAs in VAT. In conclusion, SAT and VAT are two distinct depots with regard to FA composition and expression of key lipogenic genes. However, the small differences between sSAT and dSAT suggest that FA metabolism of SAT is rather homogenous.

Lipophilic index, kidney function, and kidney function decline.

BACKGROUND AND AIMS: Unhealthy dietary fats are associated with faster kidney function decline. The cell membrane composition of phospholipid fatty acids (FAs) is a determinant of membrane fluidity and rheological properties. These properties, which have been linked to kidney damage, are thought to be reflected by the lipophilic index (LI). We prospectively investigated the associations of LI with kidney function and its decline. METHODS AND RESULTS: Observational study from the Prospective Investigation of Vasculature in Uppsala Seniors including 975 men and women with plasma phospholipid FAs composition and cystatin-C estimate glomerular filtration rate (eGFR). Of these, 780 attended re-examination after 5 years, and eGFR changes were assessed. Participants with a 5-year eGFR reduction ≥30% were considered chronic kidney disease (CKD) progressors (n = 198). LI was calculated as the sum of the products of the FA proportions with the respective FAs melting points. Blood rheology/viscosity measurements were performed in a random subsample of 559 subjects at baseline. Increased LI showed a statistically significant but overall weak association with blood, plasma viscosity (both Spearman rho = 0.16, p < 0.01), and erythrocyte deformability (rho = -0.09, p < 0.05). In cross-sectional analyses, LI associated with lower eGFR (regression coefficient 3.00 ml/min/1.73 m2 1-standard deviation (SD) increment in LI, 95% CI: -4.31, -1.69, p < 0.001). In longitudinal analyses, LI associated with a faster eGFR decline (-2.13 [95% CI -3.58, -0.69] ml/min/1.73 m2, p < 0.01) and with 32% increased odds of CKD progression (adjusted OR 1.32 [95%, CI 1.05-1.65]). CONCLUSIONS: A high LI was associated with lower kidney function, kidney function decline, and CKD progression.

Prediction of cardiovascular disease by abdominal obesity measures is dependent on body weight and sex--results from two community based cohort studies.

AIM: To study waist-hip ratio (WHR), waist circumference (WC), sagittal abdominal diameter (SAD), and waist-hip-height ratio (WHHR) as predictors of CVD, in men and women stratified by BMI (cut-off ≥25). METHODS AND RESULTS: A cohort of n = 3741 (53% women) 60-year old individuals without CVD was followed for 11-years (375 CVD cases). To replicate the results, we also assessed another large independent cohort; The Malmö Diet and Cancer study - cardiovascular cohort (MDCC, (n = 5180, 60% women, 602 CVD cases during 16-years). After adjustment for established risk factors in normal-weight women, the hazard ratio (HR) per one standard deviation (SD) were; WHR; 1.91 (95% confidence interval (CI) 1.35-2.70), WC; 1.81 (95% CI 1.02-3.20), SAD; 1.25 (95% CI 0.74-2.11), and WHHR; 1.97 (95% CI 1.40-2.78). In men the association with WHR, WHHR and WC were not significant, whereas SAD was the only measure that significantly predicted CVD in men (HR 1.19 (95% CI 1.04-1.35). After adjustments for established risk factors in overweight/obese women, none of the measures were significantly associated with CVD risk. In men, however, all measures were significant predictors; WHR; 1.24 (955 CI 1.04-1.47), WC 1.19 (95% CI 1.00-1.42), SAD 1.21 (95% CI 1.00-1.46), and WHHR; 1.23 (95% CI 1.05-1.44). Only the findings in men with BMI ≥ 25 were verified in MDCC. CONCLUSION: In normal weight individuals, WHHR and WHR were the best predictors in women, whereas SAD was the only independent predictor in men. Among overweight/obese individuals all measures failed to predict CVD in women, whereas WHHR was the strongest predictor after adjustments for CVD risk factors in men.

Serum fatty acid patterns, insulin sensitivity and the metabolic syndrome in individuals with chronic kidney disease.

OBJECTIVES: The causes of the multiple metabolic disorders of individuals with chronic kidney disease (CKD) are not fully known. We investigated the relationships between dietary fat quality, the metabolic syndrome (MetS), insulin sensitivity and inflammation in individuals with CKD. SUBJECTS: Two population-based surveys were conducted in elderly Swedish individuals (aged 70 years) with serum cystatin C-estimated glomerular filtration rate <60 mL min(-1) /1.73 m2: the Uppsala Longitudinal Study of Adult Men (ULSAM) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) surveys. The present population comprised 274 men and 187 subjects (63% women) from the ULSAM and PIVUS cohorts, respectively. DESIGN: Factor analyses of serum fatty acids were used to evaluate dietary fat quality. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance (IR) and, in ULSAM, also by euglycaemic clamp. RESULTS: Factor analyses generated two fatty acid patterns of (i) low linoleic acid (LA)/high saturated fatty acid (SFA) or (ii) high n-3 polyunsaturated fatty acid (n-3 PUFA) levels. In both surveys, the low LA/high SFA pattern increased the odds of having MetS [adjusted odds ratio 0.60 [95% confidence interval (CI) 0.44-0.81] and 0.45 (95% CI 0.30-0.67) per SD decrease in factor score in the ULSAM and PIVUS surveys, respectively] and was directly associated with both IR and C-reactive protein. The n-3 PUFA pattern was not consistently associated with these risk factors. CONCLUSIONS: A serum fatty acid pattern reflecting low LA and high SFA was strongly associated with MetS, IR and inflammation in two independent surveys of elderly individuals with CKD. At present, there are no specific dietary guidelines for individuals with CKD; however, these findings indirectly support current recommendations to replace SFAs with PUFAs from vegetable oils.

Novel and established anthropometric measures and the prediction of incident cardiovascular disease: a cohort study.

OBJECTIVES: The aim of this study was to compare novel and established anthropometrical measures in their ability to predict cardiovascular disease (CVD), and to determine whether they improve risk prediction beyond classical risk factors in a cohort study of 60-year-old men and women. We also stratified the results according to gender to identify possible differences between men and women. Furthermore, we aimed to replicate our findings in a large independent cohort (The Malmö Diet and Cancer study-cardiovascular cohort). METHODS: This was a population-based study of 1751 men and 1990 women, aged 60 years and without CVD at baseline, with 375 incident cases of CVD during 11 years of follow-up. Weight, height, waist circumference (WC), hip circumference and sagittal abdominal diameter (SAD) were measured at baseline. Body mass index (BMI), waist-hip ratio (WHR), waist-hip-height ratio (WHHR), WC-to-height ratio (WCHR) and SAD-to-height ratio (SADHR) were calculated. RESULTS: All anthropometric measures predicted CVD in unadjusted Cox regression models per s.d. increment (hazard ratios, 95% confidence interval), while significant associations after adjustments for established risk CVD factors were noted for WHHR 1.20 (1.08-1.33), WHR 1.14 (1.02-1.28), SAD 1.13 (1.02-1.25) and SADHR 1.17 (1.06-1.28). WHHR had higher increases in C-statistics, and model improvements (likelihood ratio tests (P<0.001)). In the replication study (MDC-CC, n=5180), WHHR was the only measure that improved Cox regression models in men (P=0.01). CONCLUSION: WHHR, a new measure reflecting body fat distribution, showed the highest risk estimates after adjustments for established CVD risk factors. These findings were verified in men but not women in an independent cohort.

A gene variation (rs12691) in the CCAT/enhancer binding protein α modulates glucose metabolism in metabolic syndrome.

BACKGROUND AND AIMS: CCAAT/enhancer-binding protein alpha (CEBPA) is a transcription factor involved in adipogenesis and energy homeostasis. Caloric restriction reduces CEBPA protein expression in patients with metabolic syndrome (MetS). A previous report linked rs12691 SNP in CEBPA to altered concentration of fasting triglycerides. Our objective was to assess the effects of rs12691 in glucose metabolism in Metabolic Syndrome (MetS) patients. METHODS AND RESULTS: Glucose metabolism was assessed by static (glucose, insulin, adiponectin, leptin and resistin plasma concentrations) and dynamic (disposition index, insulin sensitivity index, HOMA-IR and acute insulin response to glucose) indices, performed at baseline and after 12 weeks of 4 dietary interventions (high saturated fatty acid (SFA), high monounsaturated fatty acid (MUFA), low-fat and low-fat-high-n3 polyunsaturated fatty acid (PUFA)) in 486 subjects with MetS. Carriers of the minor A allele of rs12691 had altered disposition index (p = 0.0003), lower acute insulin response (p = 0.005) and a lower insulin sensitivity index (p = 0.025) indicating a lower insulin sensitivity and a lower insulin secretion, at baseline and at the end of the diets. Furthermore, A allele carriers displayed lower HDL concentration. CONCLUSION: The presence of the A allele of rs12691 influences glucose metabolism of MetS patients.

Replacing dairy fat with rapeseed oil causes rapid improvement of hyperlipidaemia: a randomized controlled study.

BACKGROUND: Rapeseed oil (RO), also known as canola oil, principally contains the unsaturated fatty acids 18:1n-9, 18:2n-6 and 18:3n-3 and may promote cardiometabolic health. OBJECTIVE: To investigate the effects on lipoprotein profile, factors of coagulation and insulin sensitivity of replacing a diet rich in saturated fat from dairy foods (DF diet) with a diet including RO-based fat (RO diet). DESIGN: During a 2×3-week randomized, controlled, cross-over trial, 20 free-living hyperlipidaemic subjects were provided with isocaloric test diets that differed in fat composition alone. Blood lipoprotein profile, coagulation and fibrinolytic factors and insulin sensitivity (euglycaemic clamp) were determined before and after the dietary intervention. RESULTS: All subjects completed the study, and compliance was high according to changes in serum fatty acids. The RO diet, but not the DF diet, reduced the levels of serum cholesterol (-17%), triglycerides (-20%) and low-density lipoprotein cholesterol (-17%), cholesterol/high-density lipoprotein (HDL) cholesterol ratio (-21%), apolipoprotein (apo) B/apo A-I ratio (-4%) and factor VII coagulant activity (FVIIc) (-5%) from baseline. These changes were significantly different between the diets (P=0.05 to P<0.0001), except for FVIIc (P=0.1). The RO diet, but not the DF diet, modestly increased serum lipoprotein(a) (+6%) and tended to increase the glucose disappearance rate (K-value, +33%). HDL cholesterol, insulin sensitivity, fibrinogen and tissue plasminogen activator inhibitor-1 levels did not change from baseline or differ between the two diets. CONCLUSIONS: In a diet moderately high in total fat, replacing dairy fat with RO causes a rapid and clinically relevant improvement in serum lipoprotein profile including lowering of triglycerides in hyperlipidaemic individuals.

Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress.

BACKGROUND AND AIMS: The Metabolic Syndrome (MetS) is associated with increased cardiovascular risk. Circulating microparticles (MP) are involved in the pathogenesis of atherothrombotic disorders and are raised in individual with CVD. We measured their level and cellular origin in subjects with MetS and analyzed their associations with 1/anthropometric and biological parameters of MetS, 2/inflammation and oxidative stress markers. METHODS AND RESULTS: Eighty-eight subjects with the MetS according to the NCEP-ATPIII definition were enrolled in a bicentric study and compared to 27 healthy controls. AnnexinV-positive MP (TMP), MP derived from platelets (PMP), erythrocytes (ErMP), endothelial cells (EMP), leukocytes (LMP) and granulocytes (PNMP) were determined by flow cytometry. MetS subjects had significantly higher counts/µl of TMP (730.6±49.7 vs 352.8±35.6), PMP (416.0±43.8 vs 250.5±23.5), ErMP (243.8±22.1 vs 73.6±19.6) and EMP (7.8±0.8 vs 4.0±1.0) compared with controls. LMP and PNMP were not statistically different between groups. Multivariate analysis demonstrated that each criterion for the MetS influenced the number of TMP. Waist girth was a significant determinant of PMP and EMP level and blood pressure was correlated with EMP level. Glycemia positively correlated with PMP level whereas dyslipidemia influenced EMP and ErMP levels. Interestingly, the oxidative stress markers, plasma glutathione peroxydase and urinary 8-iso-prostaglandin F(2) α, independently influenced TMP and PMP levels whereas inflammatory markers did not, irrespective of MP type. CONCLUSION: Increased levels of TMP, PMP, ErMP and EMP are associated with individual metabolic abnormalities of MetS and oxidative stress. Whether MP assessment may represent a marker for risk stratification or a target for pharmacological intervention deserves further investigation.

Serum cathepsin S is associated with serum C-reactive protein and interleukin-6 independently of obesity in elderly men.

OBJECTIVE: Cathepsin S has been suggested provide a mechanistic link between obesity and atherosclerosis, possibly mediated via adipose tissue-derived inflammation. Previous data have shown an association between circulating cathepsin S and inflammatory markers in the obese, but to date, community-based reports are lacking. Accordingly, we aimed to investigate the association between serum levels of cathepsin S and markers of cytokine-mediated inflammation in a community-based sample, with prespecified subgroup analyses in nonobese participants. METHODS: Serum cathepsin S, C-reactive protein (CRP), and IL-6 were measured in a community-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men; mean age 71 years, n = 991). CRP and IL-6 were also measured at a reexamination after 7 yr. RESULTS: After adjustment for age, body mass index, fasting plasma glucose, diabetes treatment, systolic blood pressure, diastolic blood pressure, hypertension treatment, serum cholesterol, serum high-density lipoprotein cholesterol, prior cardiovascular disease, smoking, and leisure time physical activity, higher cathepsin S was associated with higher CRP (regression coefficient for 1 sd increase, 0.13; 95% confidence interval 0.07-0.19; P < 0.001) and higher serum IL-6 (regression coefficient for 1 sd increase, 0.08; 95% confidence interval 0.01-0.14; P = 0.02). These associations remained similar in normal-weight participants (body mass index <25 kg/m(2), n = 375). In longitudinal analyses, higher cathepsin S at baseline was associated with higher serum CRP and IL-6 after 7 yr. CONCLUSIONS: These results provide additional evidence for the interplay between cathepsin S and inflammatory activity and suggest that this association is present also in normal-weight individuals in the community.

Serum and dietary beta-carotene and alpha-tocopherol and incidence of type 2 diabetes mellitus in a community-based study of Swedish men: report from the Uppsala Longitudinal Study of Adult Men (ULSAM) study.

AIMS/HYPOTHESIS: To investigate the association of serum concentrations and dietary intake of beta-carotene and alpha-tocopherol with type 2 diabetes incidence. METHODS: Serum beta-carotene, alpha-tocopherol, lifestyle factors (BMI, physical activity and smoking) and metabolic factors (insulin sensitivity [homeostasis model assessment], acute insulin response and impaired fasting glucose) were analysed in 846 50-year-old non-diabetic Swedish men (participants in the Uppsala Longitudinal Study of Adult Men). Diabetes was identified in 245 participants at reinvestigations after 10, 20 and 27 years. At the 20 year reinvestigation, dietary intake of beta-carotene and alpha-tocopherol, insulin sensitivity (euglycaemic-hyperinsulinaemic clamp) and insulin secretion (early insulin response in OGTT) were determined. RESULTS: The highest tertile of serum beta-carotene at age 50 (>0.335 mumol/l) was associated with 59% lower risk of diabetes during follow-up compared with the lowest tertile (<0.210 mumol/l) after adjustment for lifestyle and metabolic factors (p < 0.01). The highest tertile of lipid-corrected serum alpha-tocopherol at age 50 (>3.67 mumol/mmol) was associated with 46% lower risk of diabetes compared with the lowest tertile (<3.25 mumol/mmol) independently of metabolic factors (p < 0.05). Moreover, lower serum beta-carotene and alpha-tocopherol concentrations were independently associated with impaired insulin sensitivity (p < 0.001), but not with early insulin response, in a subsample of non-diabetic individuals 20 years later. Dietary intake of beta-carotene and alpha-tocopherol independently predicted type 2 diabetes during 7 years of follow-up. CONCLUSIONS/INTERPRETATION: Serum concentrations and dietary intakes of beta-carotene and alpha-tocopherol independently predicted insulin resistance and type 2 diabetes incidence during 27 years of follow-up in a community-based study of men. This result supports the importance of impaired antioxidant status for the development of insulin resistance and type 2 diabetes.

Fatty acid composition of serum lipids predicts the development of the metabolic syndrome in men.

AIMS/HYPOTHESIS: Types of dietary fat have been related to components of the metabolic syndrome. Serum fatty acid composition mainly reflects dietary fat intake, but also endogenous fatty acid synthesis catalysed by Delta-desaturases. It is not known whether alterations of fatty acid composition or desaturase activities predict metabolic syndrome. MATERIALS AND METHODS: We prospectively evaluated fatty acid composition in serum cholesteryl esters and estimated desaturase activities in 1,558 50-year-old men taking part in a population-based cohort study. The follow-up time was 20 years. Stearoyl-CoA desaturase (SCD-1), Delta6 (D6D) and Delta5 (D5D) desaturases were estimated as precursor to fatty acid ratios. RESULTS: High activity of estimated SCD-1 (odds ratio=1.29, p<0.05) and D6D (odds ratio=1.35, p<0.05), as well as low estimated D5D activity (odds ratio=0.71, p<0.001) predicted the development of metabolic syndrome (as defined by the National Cholesterol Education Program). The predictive value of D5D activity was independent of lifestyle factors (smoking, BMI and physical activity), whereas the risk associated with higher SCD-1 and D6D activities was mainly explained by obesity. Among those developing metabolic syndrome (119 out of 706) during follow-up, the proportions of fatty acids 14:0, 16:0, 16:1 (n-7), 18:1 (n-9), 18:3 (n-6) and 20:3 (n-6) were increased at baseline, while 18:2 (n-6) was decreased (p<0.05 for all). CONCLUSIONS/INTERPRETATION: Serum fatty acid composition predicts the long-term development of the metabolic syndrome, and D5D activity may be particularly important in this process. Our results suggest a role of dietary fat quality in the development of metabolic syndrome, but the possibility that altered fatty acid composition, partly secondary to genetic or hormonal factors, should also be considered.

Conjugated linoleic acid induces lipid peroxidation in men with abdominal obesity.

Conjugated linoleic acid (CLA) has been shown in experimental studies to have chemoprotective properties, and may decrease the deposition of body fat. CLA is prone to oxidation, and it has been suggested that increased lipid oxidation may contribute to the anti-tumorigenic effects of this agent. The present study investigates the urinary levels of 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)), a major isoprostane, and of 15-oxo-dihydro-PGF(2alpha), a major metabolite of PGF(2alpha), as indicators of non-enzymic and enzymic arachidonic acid oxidation respectively after dietary supplementation with CLA in middle-aged men (mean age 53 years) with abdominal obesity for 1 month in a randomized controlled trial. Significant increases in the levels of both 8-iso-PGF(2alpha) and 15-oxo-dihydro-PGF(2alpha) in urine (P<0. 0001 and P=0.0013 respectively) were observed after 1 month of daily CLA intake (4.2 g/day) as compared with the control group. The lipid peroxidation parameters had returned to their basal levels at 2 weeks after the cessation of CLA intake, and remained at the same levels for a further 2 weeks until the end of the study. CLA had no effect on serum alpha-tocopherol and gamma-tocopherol levels, or on the urinary levels of 2,3-dinor-thromboxane B(2). Thus CLA may induce both non-enzymic and enzymic lipid peroxidation in vivo in middle-aged men with abdominal obesity, without any side effects. The consequences of the increased lipid peroxidation after CLA supplementation are unknown.