Comparison of the accuracy of commercial two-point and multi-echo Dixon MRI for quantification of fat in liver, paravertebral muscles, and vertebral bone marrow.

PURPOSE: Excess fat accumulation contributes significantly to metabolic dysfunction and diseases. This study aims to systematically compare the accuracy of commercially available Dixon techniques for quantification of fat fraction in liver, skeletal musculature, and vertebral bone marrow (BM) of healthy individuals, investigating biases and sex-specific influences. METHOD: 100 healthy White individuals (50 women) underwent abdominal MRI using two-point and multi-echo Dixon sequences. Fat fraction (FF), proton density fat fraction (PDFF) and T2* values were calculated for liver, paravertebral muscles (PVM) and vertebral BM (Th8-L5). Agreement and systematic deviations were assessed using linear correlation and Bland-Altman plots. RESULTS: High correlations between FF and PDFF were observed in liver (r = 0.98 for women; r = 0.96 for men), PVM (r = 0.92 for women; r = 0.93 for men) and BM (r = 0.97 for women; r = 0.95 for men). Relative deviations between FF and PDFF in liver (18.92 % for women; 13.32 % for men) and PVM (1.96 % for women; 11.62 % for men) were not significant. Relative deviations in BM were significant (38.13 % for women; 27.62 % for men). Bias correction using linear models reduced discrepancies. T2* times were significantly shorter in BM (8.72 ms for women; 7.26 ms for men) compared to PVM (13.45 ms for women; 13.62 ms for men) and liver (29.47 ms for women; 26.35 ms for men). CONCLUSION: While no significant differences were observed for liver and PVM, systematic errors in BM FF estimation using two-point Dixon imaging were observed. These discrepancies - mainly resulting from organ-specific T2* times - have to be considered when applying two-point Dixon approaches for assessment of fat content. As suitable correction tools, linear models could provide added value in large-scale epidemiological cohort studies. Sex-specific differences in T2* should be considered.

The Acute Cytokine Response to 30-Minute Exercise Bouts Before and After 8-Week Endurance Training in Individuals With Obesity.

CONTEXT: One acute bout of exercise leads to a rapid increase in the systemic cytokine concentration. Regular exercise might alter the cytokine response, in particular in beforehand untrained and obese individuals. OBJECTIVE: Using a proximity extension assay, we studied the effects of acute exercise as well as endurance training on a panel of 92 cytokines related to inflammation. METHODS: A total of 22 individuals (30 ± 9 years; peak oxygen uptake [VO2peak] 25.2 ± 4.2 mL/[kg × min]; body mass index [BMI] 31.7 ± 4.4) participated in an 8-week endurance exercise intervention. Blood samples were collected before and immediately after 30 minutes' ergometer exercise at 80% VO2peak. RESULTS: Before and after the training intervention, 40 and 37 cytokines, respectively, were acutely increased more than 1.2-fold (Benjamini-Hochberg [BH]-adjusted P < .05). The exercise intervention did not change the acute increase in cytokines nor the resting cytokine levels, whereas fitness was improved and adiposity reduced. The increase in fitness led to a slight increase in power output when exercising at the same heart rate, which might explain the comparable increase in cytokines before and after the intervention. The largest acute increase was found for OSM, TGFA, CXCL1 and 5, and TNFSF14 (≥ 1.9-fold, BH-adjusted P < .001). The transcript levels of these proteins in whole blood were also elevated, particularly in the trained state. Only the acute increase in IL6 (1.3-fold) was related to the increase in lactate, confirming the lactate-driven secretion of IL6. CONCLUSION: Our comprehensive proteomics approach detected several underexplored serum exerkines with up to now less understood function in the adaptation to exercise.

Population-based cohort imaging: skeletal muscle mass by magnetic resonance imaging in correlation to bioelectrical-impedance analysis.

BACKGROUND: Skeletal muscle mass is subjected to constant changes and is considered a good predictor for outcome in various diseases. Bioelectrical-impedance analysis (BIA) and magnetic resonance imaging (MRI) are approved methodologies for its assessment. However, muscle mass estimations by BIA may be influenced by excess intramuscular lipids and adipose tissue in obesity. The objective of this study was to evaluate the feasibility of quantitative assessment of skeletal muscle mass by MRI as compared with BIA. METHODS: Subjects from a population-based cohort underwent BIA (50 kHz, 0.8 mA) and whole-body MRI including chemical-shift encoded MRI (six echo times). Abdominal muscle mass by MRI was quantified as total and fat-free cross-sectional area by a standardized manual segmentation-algorithm and normalized to subjects' body height2 (abdominal muscle mass indices: AMMIMRI ). RESULTS: Among 335 included subjects (56.3 ± 9.1 years, 56.1% male), 95 (28.4%) were obese (BMI ≥ 30 kg/m2 ). MRI-based and BIA-based measures of muscle mass were strongly correlated, particularly in non-obese subjects [r < 0.74 in non-obese (P < 0.001) vs. r < 0.56 in obese (P < 0.001)]. Median AMMITotal(MRI) was significantly higher in obese as compared with non-obese subjects (3246.7 ± 606.1 mm2 /m2 vs. 2839.0 ± 535.8 mm2 /m2 , P < 0.001, respectively), whereas the ratio AMMIFat-free /AMMITotal (by MRI) was significantly higher in non-obese individuals (59.3 ± 10.1% vs. 53.5 ± 10.6%, P < 0.001, respectively). No significant difference was found regarding AMMIFat-free(MRI) (P = 0.424). In analyses adjusted for age and sex, impaired glucose tolerance and measures of obesity were significantly and positively associated with AMMITotal(MRI) and significantly and inversely with the ratio AMMIFat-free(MRI) /AMMITotal(MRI) (P < 0.001). CONCLUSIONS: MRI-based assessment of muscle mass is feasible in population-based imaging and strongly correlated with BIA. However, the observed weaker correlation in obese subjects may explain the known limitation of BIA in obesity and promote MRI-based assessments. Thus, skeletal muscle mass parameters by MRI may serve as practical imaging biomarkers independent of subjects' body weight.

A comparison of emulsifiers for the formation of oil-in-water emulsions: stability of the emulsions within 9 h after production and MR signal properties.

OBJECTIVE: To provide a basis for the selection of suitable emulsifiers in oil-in-water emulsions used as tissue analogs for MRI experiments. Three different emulsifiers were investigated with regard to their ability to stabilize tissue-like oil-in-water emulsions. Furthermore, MR signal properties of the emulsifiers themselves and influences on relaxation times and ADC values of the aqueous phase were investigated. MATERIALS AND METHODS: Polysorbate 60, sodium dodecyl sulfate (SDS) and soy lecithin were used as emulsifiers. MR characteristics of emulsifiers were assessed in aqueous solutions and their function as a stabilizer was examined in oil-in-water emulsions of varying fat content (10, 20, 30, 40, 50%). Stability and homogeneity of the oil-in-water emulsions were evaluated with a delay of 3 h and 9 h after preparation using T1 mapping and visual control. Signal properties of the emulsifiers were investigated by 1H-MRS in aqueous emulsifier solutions. Relaxometry and diffusion weighted MRI (DWI) were performed to investigate the effect of various emulsifier concentrations on relaxation times (T1 and T2) and ADC values of aqueous solutions. RESULTS: Emulsions stabilized by polysorbate 60 or soy lecithin were stable and homogeneous across all tested fat fractions. In contrast, emulsions with SDS showed a significantly lower stability and homogeneity. Recorded T1 maps revealed marked creaming of oil droplets in almost all of the emulsions with SDS. The spectral analysis showed several additional signals for polysorbate and SDS. However, lecithin remained invisible in 1H-MRS. Relaxometry and DWI revealed different influences of the emulsifiers on water: Polysorbate and SDS showed only minor effects on relaxation times and ADC values of aqueous solutions, whereas lecithin showed a strong decrease in both relaxation times (r1,lecithin = 0.11 wt.%-1 s-1, r2,lecithin = 0.57 wt.%-1 s-1) and ADC value (Δ(ADC)lecithin = - 0.18 × 10-3 mm2/s⋅wt.%) with increasing concentration. CONCLUSION: Lecithin is suggested as the preferred emulsifier of oil-in-water emulsions in MRI as it shows a high stabilizing ability and remains invisible in MRI experiments. In addition, lecithin is suitable as an alternative means of adjusting relaxation times and ADC values of water.

Free fatty acids, glicentin and glucose-dependent insulinotropic polypeptide as potential major determinants of fasting substrate oxidation.

The selection of carbohydrates or fat to generate intracellular energy is thought to be crucial for long-term metabolic health. While most studies assess fuel selection after a metabolic challenge, the determinants of substrate oxidation in the fasted state remain largely unexplored. We therefore assessed the respiratory quotient by indirect calorimetry as a read-out for substrate oxidation following an overnight fast. This cross-sectional analysis consisted of 192 (92 women, 100 men) either lean or obese participants. Following an overnight fast, the respiratory quotient (RQ) was assessed, after which a 5-point 75-g oral glucose tolerance test was performed. Unlike glucose and insulin, fasting free fatty acids (FFA) correlated negatively with fasting RQ (p < 0.0001). Participants with high levels of the ketone body ß-hydroxybutyric acid had significantly lower RQ values. Fasting levels of glucose-dependent insulinotropic polypeptide (GIP) and glicentin were positively associated with fasting RQ (all p ≤ 0.03), whereas GLP-1 showed no significant association. Neither BMI, nor total body fat, nor body fat distribution correlated with fasting RQ. No relationship between the RQ and diabetes or the metabolic syndrome could be observed. In the fasting state, FFA concentrations were strongly linked to the preferentially oxidized substrate. Our data did not indicate any relationship between fasting substrate oxidation and metabolic diseases, including obesity, diabetes, and the metabolic syndrome. Since glicentin and GIP are linked to fuel selection in the fasting state, novel therapeutic approaches that target these hormones may have the potential to modulate substrate oxidation.

Resolution of severe hepatosteatosis in a cystic fibrosis patient with multifactorial choline deficiency: A case report.

In cystic fibrosis (CF), 85% to 90% of patients develop exocrine pancreatic insufficiency. Despite enzyme substitution, low pancreatic phospholipase A2 (sPLaseA2-IB) activity causes fecal loss of bile phosphatidylcholine and choline deficiency. We report on a female patient who has CF and progressive hepatosteatosis from 4.5 y onward. At 22.3 y, the liver comprised 27% fat (2385 mL volume) and transaminases were strongly increased. Plasma choline was 1.9 µmol/L (normal: 8-12 mol/L). Supplementation with 3 ×  1g/d choline chloride decreased liver fat and volume (3 mo: 8.2%; 1912 mL) and normalized transaminases. Plasma choline increased to only 5.6 µmol/L upon supplementation, with high trimethylamine oxide levels (12-35 µmol/L; normal: 3 ± 1 mol/L) proving intestinal microbial choline degradation. The patient was homozygous for rs12325817, a frequent single-nucleotide polymorphism in the PEMT gene, associated with severe hepatosteatosis in response to choline deficiency. Resolution of steatosis required 2 y (4.5% fat). Discontinuation/resumption of choline supplementation resulted in rapid relapse/resolution of steatosis, increased transaminases, and abdominal pain.

Noninvasive, longitudinal imaging-based analysis of body adipose tissue and water composition in a melanoma mouse model and in immune checkpoint inhibitor-treated metastatic melanoma patients.

BACKGROUND: As cancer cachexia (CC) is associated with cancer progression, early identification would be beneficial. The aim of this study was to establish a workflow for automated MRI-based segmentation of visceral (VAT) and subcutaneous adipose tissue (SCAT) and lean tissue water (LTW) in a B16 melanoma animal model, monitor diseases progression and transfer the protocol to human melanoma patients for therapy assessment. METHODS: For in vivo monitoring of CC B16 melanoma-bearing and healthy mice underwent longitudinal three-point DIXON MRI (days 3, 12, 17 after subcutaneous tumor inoculation). In a prospective clinical study, 18 metastatic melanoma patients underwent MRI before, 2 and 12 weeks after onset of checkpoint inhibitor therapy (CIT; n = 16). We employed an in-house MATLAB script for automated whole-body segmentation for detection of VAT, SCAT and LTW. RESULTS: B16 mice exhibited a CC phenotype and developed a reduced VAT volume compared to baseline (B16 - 249.8 µl, - 25%; controls + 85.3 µl, + 10%, p = 0.003) and to healthy controls. LTW was increased in controls compared to melanoma mice. Five melanoma patients responded to CIT, 7 progressed, and 6 displayed a mixed response. Responding patients exhibited a very limited variability in VAT and SCAT in contrast to others. Interestingly, the LTW was decreased in CIT responding patients (- 3.02% ± 2.67%; p = 0.0034) but increased in patients with progressive disease (+ 1.97% ± 2.19%) and mixed response (+ 4.59% ± 3.71%). CONCLUSION: MRI-based segmentation of fat and water contents adds essential additional information for monitoring the development of CC in mice and metastatic melanoma patients during CIT or other treatment approaches.

Dietary Rapeseed Oil Supplementation Reduces Hepatic Steatosis in Obese Men-A Randomized Controlled Trial.

SCOPE: Effective treatment for obesity associated non-alcoholic fatty liver disease (NAFLD) is limited. Dietary supplementation of n-3 polyunsaturated fatty acids, specifically alpha linolenic acid (ALA), can resolve intrahepatic lipid content (IHL). This study investigates the effect of daily supplementation of either refined rapeseed (RA), containing high amounts of ALA, or refined olive (OL) oil on IHL and glucose metabolism in NAFLD patients. METHODS AND RESULTS: 27 obese men consumed an isocaloric diet including either 50 g of RA or OL daily for 8 weeks. Hepatic proton magnetic resonance spectroscopy, hyperinsulinemic-euglycemic clamp studies and blood tests are performed before and at the end of the study. At 8 weeks a significant reduction in IHL is observed for RA (13.1 ± 1.6 before versus 11.1 ± 1.6% after intervention) versus OL (13.3 ± 2.5 before versus 15.7 ± 2.7% after intervention). For RA, a 21% reduction (P < 0.02) in serum free fatty acids (FFA) and a 1.68-fold increase (P = 0.03) of serum interleukin-6 (IL-6) is observed after 8 weeks. CONCLUSION: RA has a beneficial effect on hepatic lipid metabolism as shown by reduced IHL and serum FFA. RA induced IL-6 production seems to be liver protective confirming previous results.

High-protein diet more effectively reduces hepatic fat than low-protein diet despite lower autophagy and FGF21 levels.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent and nutrition intervention remains the most important therapeutic approach for NAFLD. Our aim was to investigate whether low- (LP) or high-protein (HP) diets are more effective in reducing liver fat and reversing NAFLD and which mechanisms are involved. METHODS: 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500-1600 kcal/day) diet groups, a low protein (10E% protein) and a high protein (30E% protein), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery. RESULTS: IHL levels decreased by 42.6% in the HP group, but were not significantly changed in the LP group despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA-seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of ß-oxidation genes did not increase in the HP group. CONCLUSIONS: HP diet more effectively reduces hepatic fat than LP diet despite of lower autophagy and FGF21. Our data suggest that liver fat reduction upon HP diets result primarily from suppression of fat uptake and lipid biosynthesis.

Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals.

CONTEXT: Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis. OBJECTIVE: We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype × pancreatic fat interactions on insulin secretion. DESIGN: Two observational studies. SETTING: University hospital. PATIENTS OR PARTICIPANTS: A total of 360 nondiabetic individuals with elevated risk for T2D (Tuebingen Family Study [TUEF]), and 64 patients undergoing pancreatectomy (Pancreas Biobank [PB], HbA1c <9%, no insulin therapy). MAIN OUTCOME MEASURES: Insulin secretion calculated from 5-point oral glucose tolerance test (TUEF) and fasting blood collection before surgery (PB). A genome-wide polygenic score for T2D was computed from 484,788 genotyped variants. The interaction of magnetic resonance imaging-measured and histologically quantified pancreatic fat with the polygenic score was investigated. Partitioned risk scores using genome-wide significant variants were also computed to gain insight into potential mechanisms. RESULTS: Pancreatic steatosis interacted with genome-wide polygenic score on insulin secretion (P = 0.003), which was similar in the replication cohort with histological measurements (P = 0.03). There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk, whereas individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. Consistent interactions were found with insulin resistance-specific and a liver/lipid-specific polygenic scores. CONCLUSIONS: The associations suggest that pancreatic steatosis only impairs beta-cell function in subjects at high genetic risk for diabetes. Genetically determined insulin resistance specifically renders pancreatic fat deleterious for insulin secretion.

Vertebral Bone Marrow Fat Is independently Associated to VAT but Not to SAT: KORA FF4-Whole-Body MR Imaging in a Population-Based Cohort.

The objective of the current study was to assess the relationship of bone marrow adipose tissue (BMAT) content to abdominal fat depots, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), as well as cardiovascular risk factors (CVRF) beyond physical activity in a population-based cohort study undergoing whole-body magnetic resonance (MR) imaging. Subjects of the Cooperative Health Research in the Augsburg Region (KORA) FF4 study without known cardiovascular disease underwent fat fraction quantification in vertebrae (BMATL1/L2) via a 2-point T1-weighted volumetric interpolated breath-hold examination (VIBE) Dixon sequence. The same MR sequence was applied to quantify VAT and SAT volume. Subjects' characteristics, including physical activity, were determined through standardized exams and self-assessment questionnaires. Univariate and multivariate linear regression were applied. In the cohort of 378 subjects (56 ± 9.1years; 42.1% female), BMATL1/L2 was 54.3 ± 10.1%, VAT was 4.54 ± 2.71 L, and SAT was 8.10 ± 3.68 L. VAT differed significantly across BMATL1/L2 tertiles (3.60 ± 2.76 vs. 4.92 ± 2.66 vs. 5.11 ± 2.48; p < 0.001), there was no significant differences for SAT (p = 0.39). In the fully adjusted model, VAT remained positively associated with BMATL1/L2 (ß = 0.53, p = 0.03). Furthermore, BMATL1/L2 was associated with age (ß = 5.40 per 10-years, p < 0.001), hemoglobin A1c (HbA1c; ß = 1.55 per 1%, p = 0.04), lipids (ß = 0.20 per 10 mg/dL triglycerides; ß = 0.40 per 10 mg/dL low-density lipoprotein (LDL); ß =-3.21 lipid-lowering medication; all p < 0.05), and less physical activity (ß = 3.7 "no or nearly no exercise" as compared to "≥2 h per week, regularly", p = 0.003); gender was not significantly different (p = 0.57). In the population-based cohort, VAT but not SAT were associated with higher BMATL1/L2 independently of physical activity and other cardiovascular risk factors. Further, BMATL1/L2 increased with older age, less physical activity, higher HbA1c, and increased lipids but decreased with lipid-lowering medication.

Brain insulin sensitivity is linked to adiposity and body fat distribution.

Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.

Bone marrow fat fraction assessment in regard to physical activity: KORA FF4-3-T MR imaging in a population-based cohort.

OBJECTIVES: To establish the effect of different degrees and kinds of physical activity on bone marrow fat (BMAT) content at different anatomical locations in a population-based cohort study undergoing whole-body MR imaging. METHODS: Subjects of the KORA FF4 study without known cardiovascular disease underwent BMAT fat fraction (FF) quantification in L1 and L2 vertebrae and femoral heads/necks (hip) via a 2-point T1-weighted VIBE Dixon sequence. BMAT-FF was calculated as mean value (fat image) divided by mean value (fat + water image). Physical activity was determined by self-assessment questionnaire regarding time spent exercising, non-exercise walking, non-exercise cycling, and job-related physical activity. RESULTS: A total of 385 subjects (96% of 400 available; 56 ± 9.1 years; 58% male) were included in the analysis. Exercise was distributed quite evenly (29% > 2 h/week; 31% ~ 1 h/week (regularly); 15% ~ 1 h/week (irregularly); 26% no physical activity). BMAT-FF was 52.6 ± 10.2% in L1, 56.2 ± 10.3% in L2, 87.4 ± 5.9% in the right hip, and 87.2 ± 5.9% in the left hip (all p < 0.001). Correlation of BMAT-FF between spine and hip was only moderate (r 0.42 to 0.46). Spinal BMAT-FF, but not hip BMAT-FF, was inversely associated with exercise > 2 h/week (p ≤ 0.02 vs. p ≥ 0.35, respectively). These associations remained significant after adjusting for age, gender, waist circumference, and glucose tolerance. No coherent association was found between BMAT-FF and physical activity in the less active groups. CONCLUSIONS: In our study, exercise was inversely correlated with vertebral BMAT-FF, but not hip BMAT-FF, when exercising for more than 2 h per week. Physical activity seems to affect the spine at least preferentially compared to the hip. KEY POINTS: • In our population-based cohort, at least 2 h of physical activity per week were required to show lower levels of bone marrow adipose tissue fat fraction in MRI. • Physical activity seems to affect bone marrow adipose tissue at least preferentially at the spine in contrast to the proximal femur.

Predictive effect of GIPR SNP rs10423928 on glucose metabolism liver fat and adiposity in prediabetic and diabetic subjects.

The gastric inhibitory polypeptide receptor (GIPR) regulates postprandial metabolism. In this context GIPR SNP rs10423928 seems toplay an important role in modulating glucose metabolism and insulinsensitivity. However, evidence regarding thisparticular SNP is still vague. In this study, we collected baseline data from four different dietaryintervention studies. We genotyped 424 subjects with prediabetes and 73with diabetes for GIPR SNP rs10423928 and examined its impact on glucosemetabolism, insulin sensitivity and body fat accumulation. We extended previous data by showing that carriers of the A allele withprediabetes displayed increased fasting glucose (p = 0.015). Unexpectedly,A allele carriers showed lower glucose levels 2 h (p = 0.021) after anoral glucose challenge compared to T/T homozygous individuals. A allelecarriers also showed significantly higher insulin sensitivity (p < 0.001)(assessed by Cederholm Index), indicating an enhanced ß-cell response. This study points to a potential protective role for rs10423928 inglucose metabolism and insulin sensitivity in subjects with prediabetes.Further studies are necessary to confirm these results.

Choline Supplementation in Cystic Fibrosis-The Metabolic and Clinical Impact.

BACKGROUND: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. METHODS: 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. RESULTS: Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D9-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D9-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. CONCLUSIONS: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.

Dietary Niacin Intake Predicts the Decrease of Liver Fat Content During a Lifestyle Intervention.

Niacin inhibits fatty acid flux from adipose tissue to liver, reduces hepatic triglyceride synthesis and increases hepatic lipid oxidation. Thus, niacin may have a role in the regulation of liver fat content in humans. We tested if dietary intake of niacin predicts change of liver fat content during a lifestyle intervention. To this end, we estimated the composition of diet from diaries of 202 healthy subjects at risk of type 2 diabetes undergoing lifestyle intervention comprising physical activity and diet counselling. Total-, subcutaneous- and visceral adipose tissue mass were measured by magnetic resonance (MR) tomography and liver fat content by 1H-MR spectroscopy at baseline and after 9 months of follow-up. Among fat compartments, liver fat content showed the largest decrease (-32%, p < 0.0001). High baseline niacin intake predicted a larger decrease of liver fat (p = 0.004). Subjects in the highest quartile of niacin intake at baseline also had the largest decrease of liver fat (1st:-10%; 2nd:-27%; 3rd:-35%; 4th:-37%). Among 58 subjects with nonalcoholic fatty liver disease (NAFLD) at baseline, NAFLD resolved in 23 subjects during the lifestyle intervention. For one standard deviation increase in niacin intake, the odds ratio for resolution of NAFLD was 1.77 (95% CI, 1.00-3.43). High dietary niacin intake may have a favorable effect on the reduction of liver fat during lifestyle intervention.

A Polygenic Risk Score of Lipolysis-Increasing Alleles Determines Visceral Fat Mass and Proinsulin Conversion.

CONTEXT: Primary dysregulation of adipose tissue lipolysis caused by genetic variation and independent of insulin resistance could explain unhealthy body fat distribution and its metabolic consequences. OBJECTIVE: To analyze common single nucleotide polymorphisms (SNPs) in 48 lipolysis-, but not insulin-signaling-related genes, to form polygenic risk scores of lipolysis-associated SNPs, and to investigate their effects on body fat distribution, glycemia, insulin sensitivity, insulin secretion, and proinsulin conversion. STUDY DESIGN, PARTICIPANTS, AND METHODS: SNP array, anthropometric, and metabolic data were available from up to 2789 participants without diabetes of the Tübingen Family study of type 2 diabetes characterized by oral glucose tolerance tests. In a subgroup (n = 942), magnetic resonance measurements of body fat stores were available. RESULTS: We identified insulin-sensitivity-independent nominal associations (P < 0.05) of SNPs in 10 genes with plasma free fatty acids (FFAs), in 7 genes with plasma glycerol and in 6 genes with both, plasma FFAs and glycerol. A score formed of the latter SNPs (in ADCY4, CIDEA, GNAS, PDE8B, PRKAA1, PRKAG2) was associated with plasma FFA and glycerol measurements (1.4*10-9 ≤ P ≤ 1.2*10-5), visceral adipose tissue mass (P = 0.0326), and proinsulin conversion (P ≤ 0.0272). The more lipolysis-increasing alleles a subject had, the lower was the visceral fat mass and the lower the proinsulin conversion. CONCLUSIONS: We found evidence for a genetic basis of adipose tissue lipolysis resulting from common SNPs in CIDEA, AMP-activated protein kinase subunits, and cAMP signaling components. A genetic score of lipolysis-increasing alleles determined lower visceral fat mass and lower proinsulin conversion.

Characteristics and associated risk factors of diverticular disease assessed by magnetic resonance imaging in subjects from a Western general population.

OBJECTIVES: Diverticular disease represents an increasing pathology and healthcare burden worldwide. Our aim was to study the prevalence, extent and distribution of asymptomatic diverticular disease assessed by magnetic resonance imaging (MRI) in a sample of a Western population. METHODS: Subjects from a population-based cohort study who underwent 3-T MRI were analyzed for the prevalence and extent of diverticula of the colon using an isotropic VIBE-Dixon gradient-echo sequence. The extent of diverticular disease was categorized according to the number of diverticula in each colonic segment. Univariate and adjusted analyses were performed to assess associated characteristics and risk factors. RESULTS: Among 393 subjects included in the analysis (56.4 ± 9.2 years, 57.5% males), 164 (42%) had diverticular disease, with the highest prevalence in the left-sided colonic segments (93% diverticular disease in the descending and sigmoid segment). Subjects with advanced diverticular disease were older (62.1 vs. 54.4 years) and had a higher body mass index (BMI), LDL cholesterol levels and systolic blood pressure (30.2 ± 5.1 vs. 27.8 ± 4.9 kg/m2, 149.8 ± 29.3 vs. 135.2 ± 32.9 mg/dl and 128.2 ± 14.1 vs. 118.4 ± 16.1 mmHg, respectively; all p > 0.003) compared with subjects without diverticular disease. In contrast, no significant correlation could be found for gender, physical activity, smoking status and alcohol consumption (all p > 0.31). Intra-rater reliability was excellent for all colonic segments (intra-class correlation [ICC] = 0.99-1.00), and inter-rater reliability was excellent for left- and right-sided colonic segments (ICC = 0.84-0.97). CONCLUSIONS: These findings provide insights into the disease mechanism of asymptomatic diverticular disease and may help to improve prevention of diverticulosis and its associated complications. KEY POINTS: • Overall prevalence of asymptomatic diverticular disease assessed by MRI was 42%, affecting predominantly the left-sided colon. • Asymptomatic diverticular disease was associated with age and cardiometabolic risk factors. • Magnetic resonance imaging reveals insights into the pathophysiologic mechanism of asymptomatic diverticular disease.

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion.

AIMS/HYPOTHESIS: Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver. METHODS: Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining. Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting. RESULTS: In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic pre-adipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when co-cultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1ß. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase- and Ca2+-dependent, manner. CONCLUSIONS/INTERPRETATION: These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.