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In addition to the subcutaneous and the visceral fat tissue, lipids can also be stored in non-adipose tissue such as in hepatocytes (intrahepatocellular lipids; IHCL), skeletal (intramyocellular lipids; IMCL) or cardiac muscle cells (intracardiomyocellular lipids; ICCL). Ectopic lipids are flexible fuel stores that can be depleted by physical exercise and repleted by diet. They are related to obesity and insulin resistance. Quantification of IMCL was initially performed invasively, using muscle biopsies with biochemical and/or histological analysis. ¹H-magnetic resonance spectroscopy (¹H-MRS) is now a validated method that allows for not only quantifying IMCL non-invasively and repeatedly, but also assessing IHCL and ICCL. This review summarizes the current available knowledge on the flexibility of ectopic lipids. The available evidence suggests a complex interplay between quantitative and qualitative diet, fat availability (fat mass), insulin action, and physical exercise, all important factors that influence the flexibility of ectopic lipids. Furthermore, the time frame of the intervention on these parameters (short-term vs. long-term) appears to be critical. Consequently, standardization of physical activity and diet are critical when assessing ectopic lipids in predefined clinical situations.

Background PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. Methods We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1 H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg -1 .min -1 ). Findings HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman’s correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=−0.59, p=0.0065) insulin sensitivity. Conclusions Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

Our aim was to prospectively determine whether quantitative computed tomography (CT) scores, consisting of simplified indices for liver remodeling and attenuation, may predict liver fibrosis in abdominal CT scans. This cross-sectional, prospective study was approved by the local IRB (Kantonale Ethikkommission Bern). Written informed consent was given from all patients undergoing study-MR exams. Between 02/16 and 05/17, four different liver fibrosis scores (CRL-R = caudate-right-lobe ratio, LIMV-, LIMA- and LIMVA-fibrosis score, with \"LIM\" for liver imaging morphology, \"V\" for liver vein diameter and \"A\" for attenuation) were calculated in 1534 consecutive abdominal CT scans, excluding patients with prior liver surgery and liver metastasis. Patients were invited to undergo magnetic resonance (MR) elastography as the non-invasive gold standard to evaluate liver fibrosis. MR elastography shear modulus ≥2.8 kPa was defined as beginning liver fibrosis, while ≥3.5 kPa was defined as significant liver fibrosis (which would correspond to fibrosis stage F2 or higher in histology). Cutoff values, sensitivities and specificities obtained from the receiver operating characteristics (ROC) analysis were then calculated in 141 patients who followed the invitation for MR elastography. To mitigate selection bias, prevalence was estimated in the screened total population (n = 1534) by applying the cutoff values with sensitivities and specificities calculated in the MR elastography sub-group. Positive predictive values (PPV) and negative predictive values (NPV) were then calculated. Fibrosis scores including liver vein attenuation LIMA-FS and LIMVA-FS showed higher areas under the ROC curves (0.96-0.97) than CRL-R (0.82) to detect significant liver fibrosis, while LIMV-FS showed good performance as well (0.92). The prevalence-corrected PPV were 29% for CRL-R, 70% for LIMV-FS, 76% for LIMA-FS and 82% for LIMVA-FS. CT fibrosis scores, notably LIMA-FS and LIMVA-FS, may predict significant liver fibrosis on routine abdominal CT scans.

Background The population of adult patients with early-treated phenylketonuria (PKU) following newborn screening is growing substantially. The ideal target range of blood phenylalanine (Phe) levels in adults outside pregnancy is a matter of debate. Therefore, prospective intervention studies are needed to evaluate the effects of an elevated Phe concentration on cognition and structural, functional, and neurometabolic parameters of the brain. Methods The PICO (Phenylalanine and Its Impact on Cognition) Study evaluates the effect of a 4-week Phe load on cognition and cerebral parameters in adults with early-treated PKU in a double-blind, randomized, placebo-controlled, crossover, noninferiority trial. Participants Thirty adult patients with early-treated PKU and 30 healthy controls comparable to patients with regard to age, sex, and educational level will be recruited from the University Hospitals Bern and Zurich, Switzerland. Patients are eligible for the study if they are 18 years of age or older and had PKU diagnosed after a positive newborn screening and were treated with a Phe-restricted diet starting within the first 30 days of life. Intervention: The cross-over intervention consists of 4-week oral Phe or placebo administration in patients with PKU. The study design mimics a Phe-restricted and a Phe-unrestricted diet using a double-blinded, placebo-controlled approach. Objectives The primary objective of the PICO Study is to prospectively assess whether a temporarily elevated Phe level influences cognitive performance (working memory assessed with a n-back task) in adults with early-treated PKU. As a secondary objective, the PICO Study will elucidate the cerebral (fMRI, neural activation during a n-back task; rsfMRI, functional connectivity at rest; DTI, white matter integrity; and ASL, cerebral blood flow) and neurometabolic mechanisms (cerebral Phe level) that accompany changes in Phe concentration. Cognition, and structural and functional parameters of the brain of adult patients with early-treated PKU will be cross-sectionally compared to healthy controls. All assessments will take place at the University Hospital Bern, Switzerland. Randomization Central randomization will be used to assign participants to the different treatment arms with age, sex, and center serving as the stratification factors. Randomization lists will be generated by an independent statistician. Blinding: All trial personnel other than the statistician generating the randomization list and the personnel at the facility preparing the interventional product are blinded to the assigned treatment. Discussion Using a combination of neuropsychological and neuroimaging data, the PICO Study will considerably contribute to improve the currently insufficient level of evidence on how adult patients with early-treated PKU should be managed. Trial registration The study is registered at clinicaltrials.gov ( NCT03788343 ) on the 27th of December 2018, at kofam.ch ( SNCTP000003117 ) on the 17th of December 2018, and on the International Clinical Trials Registry Platform of the WHO.

Aims/hypothesis Ectopic lipids are fuel stores in non-adipose tissues (skeletal muscle [intramyocellular lipids; IMCL], liver [intrahepatocellular lipids; IHCL] and heart [intracardiomyocellular lipids; ICCL]). IMCL can be depleted by physical activity. Preliminary data suggest that aerobic exercise increases IHCL. Data on exercise-induced changes on ICCL is scarce. Increased IMCL and IHCL have been related to insulin resistance in skeletal muscles and liver, whereas this has not been documented in the heart. The aim of this study was to assess the acute effect of aerobic exercise on the flexibility of IMCL, IHCL and ICCL in insulin-sensitive participants in relation to fat availability, insulin sensitivity and exercise capacity. Methods Healthy physically active men were included. V ⋅ O 2 max was assessed by spiroergometry and insulin sensitivity was calculated using the HOMA index. Visceral and subcutaneous fat were separately quantified by MRI. Following a standardised dietary fat load over 3 days, IMCL, IHCL and ICCL were measured using MR spectroscopy before and after a 2 h exercise session at 50–60% of V ⋅ O 2 max . Metabolites were measured during exercise. Results Ten men (age 28.9 ± 6.4 years, mean ± SD; V ⋅ O 2 max 56.3 ± 6.4 ml kg −1  min −1 ; BMI 22.75 ± 1.4 kg/m 2 ) were recruited. A 2 h exercise session resulted in a significant decrease in IMCL (−17 ± 22%, p  = 0.008) and ICCL (−17 ± 14%, p  = 0.002) and increase in IHCL (42 ± 29%, p  = 0.004). No significant correlations were found between the relative changes in ectopic lipids, fat availability, insulin sensitivity, exercise capacity or changes of metabolites during exercise. Conclusions/interpretation In this group, physical exercise decreased ICCL and IMCL but increased IHCL. Fat availability, insulin sensitivity, exercise capacity and metabolites during exercise are not the only factors affecting ectopic lipids during exercise.

Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass). To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy. Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO(2max)) using ¹H-MR-spectroscopy. Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO(2max), 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (-22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity. IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions. ClinicalTrial.gov NCT00491582.

Sucrose overfeeding increases intrahepatocellular (IHCL) and intramyocellular (IMCL) lipid concentrations in healthy subjects. We hypothesized that these effects would be modulated by diet protein/fat content. Twelve healthy men and women were studied on two occasions in a randomized, cross-over trial. On each occasion, they received a 3-day 12% protein weight maintenance diet (WM) followed by a 6-day hypercaloric high sucrose diet (150% energy requirements). On one occasion the hypercaloric diet contained 5% protein and 25% fat (low protein-high fat, LP-HF), on the other occasion it contained 20% protein and 10% fat (high protein-low fat, HP-LF). IHCL and IMCL concentrations (magnetic resonance spectroscopy) and energy expenditure (indirect calorimetry) were measured after WM, and again after HP-LF/LP-HF. IHCL increased from 25.0 ± 3.6 after WM to 147.1 ± 26.9 mmol/kg wet weight (ww) after LP-HF and from 30.3 ± 7.7 to 57.8 ± 14.8 after HP-LF (two-way ANOVA with interaction: p < 0.001 overfeeding x protein/fat content). IMCL increased from 7.1 ± 0.6 to 8.8 ± 0.7 mmol/kg ww after LP-HF and from 6.2 ± 0.6 to 6.9 ± 0.6 after HP-LF, (p < 0.002). These results indicate that liver and muscle fat deposition is enhanced when sucrose overfeeding is associated with a low protein, high fat diet compared to a high protein, low fat diet.

An amendment to this paper has been published and can be accessed via the original article.

To demonstrate that oscillating gradient spin-echo sequences can be combined with diffusion-weighted magnetic resonance spectroscopy even on clinical MR systems to study human brain at short diffusion times to provide apparent diffusion coefficients (ADCs) sensitive to a narrower cellular length scale than pulsed gradient spin-echo sequences at long diffusion time. Measurements were performed on a 3T MR system using a semiLaser sequence with diffusion-weighting realized by oscillating and pulsed gradient modules, encoding diffusion times <10 ms and >50 ms, respectively. Metabolite-cycling was included to measure metabolites and water simultaneously. The sequence was tested in a phantom and in a parieto-occipital cerebral region of interest with mixed gray/white matter content of 6 subjects. The water reference was used for phase, frequency, and eddy-current correction as well as motion compensation. ADCs were estimated by 1D sequential and 2D simultaneous fitting. Measurements in the phantom established that both sequences yield equal ADCs, independent of diffusion time, as expected for free diffusion. In contrast, averaged metabolite diffusion in vivo was found to be 1.9 times faster at short (8.3 ms) than at long (155 ms) diffusion times. The difference in ADC was found to be statistically significant for the creatines, cholines, N-acetylaspartate, myo-inositol, and glutamate. The water ADC was measured to be 1.3 times larger at short than at long diffusion time. It is demonstrated that application of oscillating gradients in diffusion-weighted MRS is feasible on clinical MR systems to establish the dependence of ADCs on diffusion times in humans. The initial results largely confirm earlier reports for mice’ and rats’ brain at short and long diffusion times. ADCs representing diffusion at short and ultra-short diffusion times are of interest to probe cellular or subcellular changes in disease. The presented methodology may thus open the door for investigation of pathophysiological changes in cell-specific microstructures in human cohorts. [Display omitted] •Pulsed and oscillating diffusion gradient elements implemented for diffusion-weighted MR spectroscopy on a clinical MR system.•Novel sequence allows probing cell-specific diffusion at long and short characteristic diffusion times.•Metabolite diffusion constants in human brain found to be significantly higher at the now accessible short diffusion times•Diffusion characteristics compare well with those known from rodent brain.

Carnosine (β-alanyl- l -histidine) is found in high concentrations in skeletal muscle and chronic β-alanine (BA) supplementation can increase carnosine content. This placebo-controlled, double-blind study compared two different 8-week BA dosing regimens on the time course of muscle carnosine loading and 8-week washout, leading to a BA dose–response study with serial muscle carnosine assessments throughout. Thirty-one young males were randomized into three BA dosing groups: (1) high–low: 3.2 g BA/day for 4 weeks, followed by 1.6 g BA/day for 4 weeks; (2) low–low: 1.6 g BA/day for 8 weeks; and (3) placebo. Muscle carnosine in tibialis - anterior (TA) and gastrocnemius (GA) muscles was measured by 1 H-MRS at weeks 0, 2, 4, 8, 12 and 16. Flushing symptoms and blood clinical chemistry were trivial in all three groups and there were no muscle carnosine changes in the placebo group. During the first 4 weeks, the increase for high–low (TA 2.04 mmol/kg ww , GA 1.75 mmol/kg ww ) was ~twofold greater than low–low (TA 1.12 mmol/kg ww , GA 0.80 mmol/kg ww ). 1.6 g BA/day significantly increased muscle carnosine within 2 weeks and induced continual rises in already augmented muscle carnosine stores (week 4–8, high–low regime). The dose–response showed a carnosine increase of 2.01 mmol/kg ww per 100 g of consumed BA, which was only dependent upon the total accumulated BA consumed (within a daily intake range of 1.6–3.2 g BA/day). Washout rates were gradual (0.18 mmol/kg ww and 0.43 mmol/kg ww /week; ~2%/week). In summary, the absolute increase in muscle carnosine is only dependent upon the total BA consumed and is not dependent upon baseline muscle carnosine, the muscle type, or the daily amount of supplemented BA.