The development of new diagnostic criteria for Alzheimer's disease (AD) requires new in vivo markers reflecting early pathological changes in the brain of patients. Magnetic resonance (MR) spectroscopy has been shown to provide useful information about the biochemical changes occurring in AD brain in vivo. The development of numerous transgenic mouse models of AD has facilitated the evaluation of early biomarkers, allowing researchers to perform longitudinal studies starting before the onset of the pathology. In addition, the recent development of high-field animal scanners enables the measurement of brain metabolites that cannot be reliably quantified at lower magnetic fields. In this report, we studied a new transgenic mouse model of AD, the 5xFAD model, by in vivo proton and phosphorus MR spectroscopy. This model, which is characterized by an early-onset and a robust amyloid pathology, developed changes in the neurochemical profile, which are typical in the human disease, i.e., an increase in myo-inositol and a decrease in N-acetylaspartate concentrations, as early as in the 40th week of age. In addition, a significant decrease in the γ-aminobutyrate concentration was observed in transgenic mice at this age compared to controls. The pseudo-first-order rate constant of the creatine kinase reaction as well as relative concentrations of phosphorus-containing metabolites were not changed significantly in the 36 and 72-week old transgenic mice. Overall, these results suggest that mitochondrial activity in the 5 × FAD mice is not substantially affected but that the model is relevant for studying early biomarkers of AD.

Background Interval cancer (IC) is a critical issue in colorectal cancer (CRC) screening. We identified factors associated with ICs after faecal immunochemical test (FIT) screening and explored the impact of lowering FIT cut-off or shortening screening interval on FIT-ICs in Flanders. Methods FIT participants diagnosed with a CRC during 2013–2018 were included. Factors associated with FIT-ICs were identified using logistic regression. Distributions of FIT results among FIT-ICs were examined. Results In total, 10,122 screen-detected CRCs and 1534 FIT-ICs were included (FIT-IC proportion of 13%). FIT-ICs occurred more frequently in women (OR 1.58 [95% CI 1.41–1.76]) and ages 70–74 (OR 1.35 [1.14–1.59]). FIT-ICs were more often right-sided (OR 3.53 [2.98–4.20]), advanced stage (stage IV: OR 7.15 [5.76–8.88]), and high grade (poorly/undifferentiated: OR 2.57 [2.08–3.18]). The majority (83–92%) of FIT-ICs would still be missed if FIT cut-off was lowered from 15 to 10 µg Hb/g or screening interval was shortened from 2 to 1 year. Conclusions FIT-ICs were more common in women, older age, right-sided location, advanced stage and high grade. In Flanders, lowering FIT cut-off (to 10 µg Hb/g) or shortening screening interval (to 1 year) would have a minimal impact on FIT-ICs.

Janssens S, Jonkers RA, Groen AK, Nicolay K, van Loon LJ, Prompers JJ. Effects of acute exercise on lipid content and dietary lipid uptake in liver and skeletal muscle of lean and diabetic rats. Am J Physiol Endocrinol Metab 309: E874 -E883, 2015. First published October 6, 2015; doi:10.1152/ajpendo.00292.2015.-Insulin resistance is associated with ectopic lipid accumulation. Physical activity improves insulin sensitivity, but the impact of exercise on lipid handling in insulin-resistant tissues remains to be elucidated. The present study characterizes the effects of acute exercise on lipid content and dietary lipid partitioning in liver and skeletal muscle of lean and diabetic rats by use of magnetic resonance spectroscopy (MRS). After baseline measurements, rats were randomized to exercise or no-exercise groups. A subset of animals was subjected to MRS directly after 1 h of treadmill running for measurement of total intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) content (n ϭ 7 lean and diabetic rats). The other animals were administered 13 C-labeled lipids orally after treadmill visit (with or without exercise) followed by MRS measurements after 4 and 24 h to determine the 13 C enrichment of IHCL and IMCL (n ϭ 8 per group). Total IHCL and IMCL content were fivefold higher in diabetic vs. lean rats (P Ͻ 0.001). Exercise did not significantly affect IHCL content but reduced IMCL by 25 Ϯ 7 and 33 Ϯ 4% in lean and diabetic rats (P Ͻ 0.05), respectively. Uptake of dietary lipids in liver and muscle was 2.3-fold greater in diabetic vs. lean rats (P Ͻ 0.05). Prior exercise did not significantly modulate dietary lipid uptake into muscle, but in liver of both lean and diabetic rats, lipid uptake was 44% reduced after acute exercise (P Ͻ 0.05). In conclusion, IMCL but not IHCL represents a viable substrate source during exercise in both lean and diabetic rats, and exercise differentially affects dietary lipid uptake in muscle and liver. lipid metabolism; exercise; diabetes; liver; skeletal muscle ONE OF THE EARLIEST DISTURBANCES in the etiology of type 2 diabetes is insulin resistance in major metabolic tissues, such as skeletal muscle and liver, which is generally accompanied by the accumulation of intramyocellular and intrahepatocellular lipids (IMCL and IHCL) (12,43,49,54,60,65,85,86).

BackgroundExcess consumption of energy-dense, high-fat Western diets contributes to the development of obesity and obesity-related disorders, such as fatty liver disease. However, not only the quantity but also the composition of dietary fat may play a role in the development of liver steatosis. The aim of this study was to determine the effects of low-stearate palm oil and high-stearate lard high-fat diets on in vivo liver lipid metabolism.MethodsWistar rats were fed with either normal chow (CON), a high-fat diet based on palm oil (HFP), or a high-fat diet based on lard (HFL). After 10 weeks of diet, magnetic resonance spectroscopy was applied for the in vivo determination of intrahepatocellular lipid content and the uptake and turnover of dietary fat after oral administration of 13C-labeled lipids. Derangements in liver lipid metabolism were further assessed by measuring hepatic very-low density lipoprotein (VLDL) secretion and ex vivo respiratory capacity of liver mitochondria using fat-derived substrates. In addition, whole-body and hepatic glucose tolerance were determined with an intraperitoneal glucose tolerance test.ResultsBoth high-fat diets induced liver lipid accumulation (p < 0.001), which was accompanied by a delayed uptake and/or slower turnover of dietary fat in the liver (p < 0.01), but without any change in VLDL secretion rates. Surprisingly, liver lipid content was higher in HFP than in HFL (p < 0.05), despite the increased fatty acid oxidative capacity in isolated liver mitochondria of HFP animals (p < 0.05). In contrast, while both high-fat diets induced whole-body glucose intolerance, only HFL impaired hepatic glucose tolerance.ConclusionHigh-fat diets based on palm oil and lard similarly impair the handling of dietary lipids in the liver, but only the high-fat lard diet induces hepatic glucose intolerance.

We aimed to elucidate the effects of caloric and non-caloric sweeteners on liver lipid metabolism in rats using in vivo magnetic resonance spectroscopy (MRS) and to determine their roles in the development of liver steatosis. Wistar rats received normal chow and either normal drinking water, or solutions containing 13% (w/v) glucose, 13% fructose, or 0.4% aspartame. After 7 weeks, in vivo hepatic dietary lipid uptake and de novo lipogenesis were assessed with proton-observed, carbon-13-edited MRS combined with 13C-labeled lipids and 13C-labeled glucose, respectively. The molecular basis of alterations in hepatic liver metabolism was analyzed in detail ex vivo using immunoblotting and targeted quantitative proteomics. Both glucose and fructose feeding increased adiposity, but only fructose induced hepatic lipid accumulation. In vivo MRS showed that this was not caused by increased hepatic uptake of dietary lipids, but could be attributed to an increase in de novo lipogenesis. Stimulation of lipogenesis by fructose was confirmed by a strong upregulation of lipogenic enzymes, which was more potent than with glucose. The non-caloric sweetener aspartame did not significantly affect liver lipid content or metabolism. In conclusion, liquid fructose more severely affected liver lipid metabolism in rats than glucose, while aspartame had no effect.