The role of C-reactive protein, adiponectin and leptin in the association between abdominal adiposity and insulin resistance in middle-aged individuals.

BACKGROUND AND AIMS: In the present study, we assessed the extent of mediation by low-grade systemic inflammation and adipokines in the association between abdominal adiposity and insulin resistance. METHODS AND RESULTS: In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity study, total body fat (TBF) was measured in all (n = 5772) participants who did not have missing data and neither used glucose-lowering medication, and abdominal subcutaneous adipose tissue (aSAT) and visceral adipose tissue (VAT) were assessed by MRI in a random subgroup (n = 2448). C-reactive protein (CRP), adiponectin, and leptin were considered as potential mediators, and insulin resistance was assessed by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Mediation by CRP, adiponectin, and leptin was studied by including the mediators to the fully adjusted linear regression model. Participants had a mean (SD) age of 56 (6) years, TBF of 36 (9) %, VAT of 119 (61) cm2 and aSAT of 300 (111) cm2. Per SD of TBF, VAT and aSAT, HOMA-IR was 64% (95% confidence interval [CI]: 59-70), 33% (95%CI: 28-42) and 20% (95%CI: 14-26) higher, respectively. The association between aSAT and HOMA-IR fully disappeared after adjustment for leptin; the association between VAT and HOMA-IR attenuated after adjustment for leptin (22%) and adiponectin (15%). No mediation was observed by CRP, and mediation estimates were similar in men and women. CONCLUSION: Where leptin fully explained the aSAT-HOMA-IR association, the VAT-HOMA-IR association was only partly explained by leptin and adiponectin similarly in men and women.

Adult weight change in relation to visceral fat and liver fat at middle age: The Netherlands epidemiology of obesity study.

OBJECTIVE: We aimed to investigate the associations between weight change during adulthood and the amount of abdominal subcutaneous fat, visceral fat, and liver fat at middle age. METHODS: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort of 6671 middle-aged men and women. We calculated the percentage of weight change during adulthood based on body weight at middle age and recalled body weight at age 20. Abdominal subcutaneous and visceral adipose tissue were assessed by magnetic resonance imaging (MRI), in addition to hepatic triglyceride content by 1H-MR spectroscopy in a random subgroup (maximum of n = 2580). With multivariable linear regression analysis, we examined the associations between categories of adult weight change, body mass index (BMI) at age 20 and measures of abdominal adiposity at middle age, adjusted for age, sex, ethnicity, lifestyle factors, menopausal status, parity, use of medication and total body fat at middle age. RESULTS: In 2399 participants (54% women), individuals who gained more than 50% of body weight during adulthood had 1.96 (95% CI: 1.64; 2.33) times more visceral adipose tissue at middle age and 2.39 (95% CI: 1.70, 3.36) times more hepatic triglyceride content than weight maintainers (weight change between -5% and 5%). Associations with abdominal subcutaneous adipose tissue were weaker: participants who gained more than 50% of their body weight had 1.54 (95% CI: 1.38, 1.72) times more abdominal subcutaneous adipose tissue compared with weight maintainers. CONCLUSIONS: In this population-based study, adult weight gain was associated with relatively more visceral adipose tissue and hepatic triglyceride content at middle age than abdominal subcutaneous adipose tissue. Overall, our study suggests that weight maintenance during adulthood plays an important role in limiting excess visceral adipose tissue and hepatic triglyceride content at middle age.

The Relation Between Adult Weight Gain, Adipocyte Volume, and the Metabolic Profile at Middle Age.

CONTEXT: Weight gain during adulthood increases cardiometabolic disease risk, possibly through adipocyte hypertrophy. OBJECTIVE: We aimed to study the specific metabolomic profile of adult weight gain, and to examine its association with adipocyte volume. METHODS: Nuclear magnetic resonance-based metabolomics were measured in the Netherlands Epidemiology of Obesity (NEO) study (n = 6347, discovery) and Oxford Biobank (n = 6317, replication). Adult weight gain was calculated as the absolute difference between body mass index (BMI) at middle age and recalled BMI at age 20 years. We performed linear regression analyses with both exposures BMI at age 20 years and weight gain, and separately with BMI at middle age in relation to 149 serum metabolomic measures, adjusted for age, sex, and multiple testing. Additionally, subcutaneous abdominal adipocyte biopsies were collected in a subset of the Oxford Biobank (n = 114) to estimate adipocyte volume. RESULTS: Mean (SD) weight gain was 4.5 (3.7) kg/m2 in the NEO study and 3.6 (3.7) kg/m2 in the Oxford Biobank. Weight gain, and not BMI at age 20 nor middle age, was associated with concentrations of 7 metabolomic measures after successful replication, which included polyunsaturated fatty acids, small to medium low-density lipoproteins, and total intermediate-density lipoprotein. One SD weight gain was associated with 386 µm3 (95% CI, 143-629) higher median adipocyte volume. Adipocyte volume was associated with lipoprotein particles specific for adult weight gain. CONCLUSION: Adult weight gain is associated with specific metabolomic alterations of which the higher lipoprotein concentrations were likely contributed by larger adipocyte volumes, presumably linking weight gain to cardiometabolic disease.

Effects of dietary macronutrients on liver fat content in adults: a systematic review and meta-analysis of randomized controlled trials.

Dietary macronutrient composition may affect hepatic liver content and its associated diseases, but the results from human intervention trials have been equivocal or underpowered. We aimed to assess the effects of dietary macronutrient composition on liver fat content by conducting a systematic review and meta-analysis of randomized controlled trials in adults. Four databases (PubMed, Embase, Web of Science, and COCHRANE Library) were systematically searched for trials with isocaloric diets evaluating the effect of dietary macronutrient composition (energy percentages of fat, carbohydrates, and protein, and their specific types) on liver fat content as assessed by magnetic resonance techniques, computed tomography or liver biopsy. Data on change in liver fat content were pooled by random or fixed-effects meta-analyses and expressed as standardized mean difference (SMD). We included 26 randomized controlled trials providing data for 32 comparisons on dietary macronutrient composition. Replacing dietary fat with carbohydrates did not result in changes in liver fat (12 comparisons, SMD 0.01 (95% CI -0.36; 0.37)). Unsaturated fat as compared with saturated fat reduced liver fat content (4 comparisons, SMD -0.80 (95% CI -1.09; -0.51)). Replacing carbohydrates with protein reduced liver fat content (5 comparisons, SMD -0.33 (95% CI -0.54; -0.12)). Our meta-analyses showed that replacing carbohydrates with total fat on liver fat content was not effective, while replacing carbohydrates with proteins and saturated fat with unsaturated fat was. More well-performed and well-described studies on the effect of types of carbohydrates and proteins on liver fat content are needed, especially studies comparing proteins with fats.

The contribution of tissue-grouped BMI-associated gene sets to cardiometabolic-disease risk: a Mendelian randomization study.

BACKGROUND: Body mass index (BMI)-associated loci are used to explore the effects of obesity using Mendelian randomization (MR), but the contribution of individual tissues to risks remains unknown. We aimed to identify tissue-grouped pathways of BMI-associated loci and relate these to cardiometabolic disease using MR analyses. METHODS: Using Genotype-Tissue Expression (GTEx) data, we performed overrepresentation tests to identify tissue-grouped gene sets based on mRNA-expression profiles from 634 previously published BMI-associated loci. We conducted two-sample MR with inverse-variance-weighted methods, to examine associations between tissue-grouped BMI-associated genetic instruments and type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD), with use of summary-level data from published genome-wide association studies (T2DM: 74 124 cases, 824 006 controls; CAD: 60 801 cases, 123 504 controls). Additionally, we performed MR analyses on T2DM and CAD using randomly sampled sets of 100 or 200 BMI-associated genetic variants. RESULTS: We identified 17 partly overlapping tissue-grouped gene sets, of which 12 were brain areas, where BMI-associated genes were differentially expressed. In tissue-grouped MR analyses, all gene sets were similarly associated with increased risks of T2DM and CAD. MR analyses with randomly sampled genetic variants on T2DM and CAD resulted in a distribution of effect estimates similar to tissue-grouped gene sets. CONCLUSIONS: Overrepresentation tests revealed differential expression of BMI-associated genes in 17 different tissues. However, with our biology-based approach using tissue-grouped MR analyses, we did not identify different risks of T2DM or CAD for the BMI-associated gene sets, which was reflected by similar effect estimates obtained by randomly sampled gene sets.

The Association between Adult Weight Gain and Insulin Resistance at Middle Age: Mediation by Visceral Fat and Liver Fat.

We aimed to investigate the role of the amount of visceral fat and liver fat in the association between adult weight change and insulin resistance at middle age. In the Netherlands Epidemiology of Obesity study, adult weight change was calculated with recalled body weight at age 20 years and measured body weight at middle age. Measures of insulin resistance were calculated using both fasting and postprandial glucose and insulin concentrations. Visceral fat was assessed by magnetic resonance (MR) imaging and liver fat by proton-MR spectroscopy (N = 1758). We examined the association between adult weight change and insulin resistance with linear regression, adjusted for confounding factors. To investigate mediation, we additionally adjusted for total body fat, visceral fat, and liver fat. In participants who gained ≥50% of body weight during adulthood, homeostatic model assessment for insulin resistance (HOMA-IR) was 3.22 (95% CI 2.76; 3.77) times higher than in weight maintainers. In a joint model, total body fat mediated this association for 8.1% (95% CI -9.2; 25.4), visceral fat for 32.0% (18.6; 45.4%) and liver fat for 22.5% (15.0; 30.1). The association between adult weight gain and insulin resistance at middle age is largely mediated by both visceral fat and liver fat.

Lipopolysaccharide Lowers Cholesteryl Ester Transfer Protein by Activating F4/80+Clec4f+Vsig4+Ly6C- Kupffer Cell Subsets.

BACKGROUND: Lipopolysaccharide (LPS) decreases hepatic CETP (cholesteryl ester transfer protein) expression albeit that the underlying mechanism is disputed. We recently showed that plasma CETP is mainly derived from Kupffer cells (KCs). In this study, we investigated the role of KC subsets in the mechanism by which LPS reduces CETP expression. METHODS AND RESULTS: In CETP-transgenic mice, LPS markedly decreased hepatic CETP expression and plasma CETP concentration without affecting hepatic macrophage number. This was paralleled by decreased expression of the resting KC markers C-type lectin domain family 4, member f (Clec4f) and V-set and immunoglobulin domain containing 4 (Vsig4), while expression of the infiltrating monocyte marker lymphocyte antigen 6 complex locus C (Ly6C) was increased. Simultaneously, the ratio of plasma high-density lipoprotein-cholesterol over non-high-density lipoprotein-cholesterol transiently increased. After ablation hepatic macrophages via injection with liposomal clodronate, the reappearance of hepatic gene and protein expression of CETP coincided with Clec4f and Vsig4, but not Ly6C. Double-immunofluorescence staining showed that CETP co-localized with Clec4f+ KCs and not Ly6C+ monocytes. In humans, microarray gene-expression analysis of liver biopsies revealed that hepatic expression and plasma level of CETP both correlated with hepatic VSIG4 expression. LPS administration decreased the plasma CETP concentration in humans. In vitro experiments showed that LPS reduced liver X receptor-mediated CETP expression. CONCLUSIONS: Hepatic expression of CETP is exclusively confined to the resting KC subset (ie, F4/80+Clec4f+Vsig4+Ly6C-). LPS activated resting KCs, leading to reduction of Clec4f and Vsig4 expression and reduction of hepatic CETP expression, consequently decreasing plasma CETP and raising high-density lipoprotein (HDL)-cholesterol. This sequence of events is consistent with the anti-inflammatory role of HDL in the response to LPS and may be relevant as a defense mechanism against bacterial infections.