Atherosclerosis Impairs Naive CD4 T-Cell Responses via Disruption of Glycolysis

Objective: CD4 T cells are important regulators of atherosclerotic progression. The metabolic profile of CD4 T cells controls their signaling and function, but how atherosclerosis affects T-cell metabolism is unknown. Here, we sought to determine the impact of atherosclerosis on CD4 T-cell metabolism and the contribution of such alterations to atheroprogression. Approach and Results: Using PCR arrays, we profiled the expression of metabolism genes in CD4 T cells from atherosclerotic, apolipoprotein-E knockout mice fed a Western diet. These cells exhibited dysregulated expression of genes critically involved in glycolysis and fatty acid degradation, compared with those from animals fed a standard laboratory diet. We examined how T-cell metabolism was changed in standard laboratory diet or Western diet–fed apolipoprotein-E knockout mice or humans by measuring glucose uptake, activation, and proliferation in CD4 T cells. We found that naive CD4 T cells from Western diet–fed apolipoprotein-E knockout mice failed to uptake glucose and thus displayed impaired proliferation and activation, compared with CD4 T cells from standard laboratory diet–fed animals. Similarly, as in mice, we observed that naive CD4 T-cell frequencies were reduced in circulation of human subjects with high cardiovascular disease compared with low cardiovascular disease, as assessed clinically based on medically necessary coronary angiography. Naive T cells from high cardiovascular disease subjects also showed reduced proliferative capacity. Conclusions: These results highlight the dysfunctional changes that occur in CD4 T-cell metabolism and immune responses during atherosclerosis. Targeting metabolic pathways within naive CD4 T cells could thus yield novel therapeutic approaches for improving CD4 T-cell responses against atheroprogression.

Impact of Maternal Food Restriction on Heart Proteome in Appropriately Grown and Growth-Restricted Wistar—Rat Offspring

Objective: Fetal growth restriction is associated with increased postnatal cardiovascular morbidity. The alterations in heart physiology and structure caused by in utero nutrient deprivation have not been extensively studied. We aim to investigate the impact of maternal food restriction on the cardiac proteome of newborn rats with normal (non-fetal growth-restricted (FGR)) and reduced (FGR) birth weight. Methods: On day 14 of gestation, 10 timed pregnant rats were randomized into two nutritional groups: (a) Standard laboratory diet and (b) 50% global food restriction. Pups born to food-restricted mothers were subdivided, based on birthweight, into fetal growth-restricted (FGR) and non-FGR, while pups born from normally nourished mothers were considered controls. Rat neonates were euthanized immediately after birth and the hearts of 11 randomly selected male offspring (n = 4 FGR, n = 4 non-FGR, n = 3 control group) were analyzed using quantitative proteomics. Results: In total, 7422 proteins were quantified (q < 0.05). Of these, 1175 were differentially expressed in FGR and 231 in non-FGR offspring vs. control with 151 common differentially expressed proteins (DEPs) between the two groups. Bioinformatics analysis of DEPs in FGR vs. control showed decreased integrin and apelin cardiac fibroblast signaling, decreased muscle contraction and glycolysis, and over-representation of a protein network related to embryonic development, and cell death and survival. Conclusion: Our study illustrates the distinct proteomic profile of FGR and non-FGR offspring of food-restricted dams underlying the importance of both prenatal adversities and birth weight in cardiac physiology and development.

Maternal and offspring high-fat diet leads to platelet hyperactivation in male mice offspring

Maternal over-nutrition increases the risk of diabetes and cardiovascular events in offspring. While prominent effects on cardiovascular health are observed, the impact on platelet physiology has not been studied. Here, we examined whether maternal high-fat diet (HF) ingestion affects the platelet function in lean and obese offspring. C57BL6/N mice dams were given a HF or control (C) diet for 8 weeks before and during pregnancy. Male and female offspring received C or HF diets for 26 weeks. Experimental groups were: C/C, dam and offspring fed standard laboratory diet; C/HF dam fed standard laboratory diet and offspring fed HF diet; HF/C and HF/HF. Phenotypic and metabolic tests were performed and blood collected for platelet studies. Compared to C/C, offspring HF groups were obese, with fat accumulation, hyperglycaemia and insulin resistance. Female offspring did not present platelet hyperactivity, hence we focused on male offspring. Platelets from HF/HF mice were larger, hyperactive and presented oxidative stress when compared to C/C. Maternal and offspring HF diet results in platelet hyperactivation in male mouse offspring, suggesting a novel ‘double-hit’ effect.

Spontaneous Atherosclerosis in Aged LCAT-Deficient Hamsters With Enhanced Oxidative Stress—Brief Report

Objective: LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT −/− ) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT −/− hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results: Young (<8 months) and aged (>16 months) male and female wild-type and LCAT −/− hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT −/− hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT −/− hamsters, the lesion areas at the aortic roots were ≈40×10 4 μm 3 in males and 18×10 4 μm 3 in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 μmol/L in males and 30 μmol/L in females, which are significantly associated with the atherosclerotic lesions. Conclusions: Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT −/− hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.

Lactobacilli in a clade ameliorate age-dependent decline of thermotaxis behavior in Caenorhabditis elegans

Diet is proposed to affect brain aging. However, the causality and mechanism of dietary effects on brain aging are still unclear due to the long time scales of aging. The nematode Caenorhabditis elegans (C. elegans) has led aging research because of its short lifespan and easy genetic manipulation. When fed the standard laboratory diet, Escherichia coli (E. coli), C. elegans experiences an age-dependent decline in temperature-food associative learning, called thermotaxis. To address if diet ameliorates this decline, we screened 35 different lactic acid bacteria as alternative diets. We found that Lactobacilli in a clade enriched with heterofermentative bacteria ameliorated age-dependent decline. On the other hand, homofermentative Lactobacillus species did not show this beneficial effect. Lactobacilli affected the thermotaxis of aged animals through DAF-16, an ortholog of mammalian FOXO transcription factor, while the effect on the thermotaxis was independent of the lifespan and locomotion. Our results demonstrate that diet can impact brain aging without changing the lifespan and that bacterial screen using C. elegans is a powerful approach to investigate age-dependent behavioral decline.

Effets hypolipidemiques de l’huile extraite du poisson Ethmalosa fimbriata chez des rattes dyslipidémiques

Les maladies cardiovasculaires sont un problème de santé publique affectant plus de 30% de la population mondiale. Une des principales causes de ces pathologies est l’hyperlipidémie. Cette étude vise à valoriser l’huile du poisson en explorant ses effets sur la dyslipidémie. 20 rattes ont été réparties en 4 groupes : le groupe 1 a reçu le régime standard de laboratoire (RSL), les Groupes 2, 3 et 4 ont reçu le RSL supplémenté au jaune d’oeuf bouilli à la dose de 5 g/j/ratte. Après 16 semaines, le groupe 3 a reçu uniquement le RSL, le roupe 4 a reçu le RSL et supplémenté à l’huile à 1 g/jr/kg pendant 3 semaines. Au terme de cette expérimentation les rattes ont été sacrifiées et les paramètres biochimiques sériques ont été dosés. Les résultats montrent que le régime hyperlipidémique a induit le surpoids, des désordres tissulaires et plasmatiques marqués par l’augmentation du cholestérol-CT, des triglycérides, du cholestérol LDL et la baisse du cholestérol HDL. Le groupe 4 a présenté une baisse significative du CT, des TG, du C-LDL et l’augmentation du C-HDL. L’huile de E. fimbriata a présenté des effets hypolipidémiques et pourrait être utilisée dans la prévention des risques cardiaques. Cette étude se poursuivra par la détermination du profil en acide gras de cette huile.Mots clés : Dyslipidémie, surpoids, hypolipidémie, hyperlipémie, lipide. English Title: Hypolipidemic effects of oil extracted from Ethmalosa fimbriata on dislipidemic female ratsCardiovascular diseases represent a public health problem which affects more than 30% of people worldwide. One principle cause of these diseases is hyperlipidemia. This study aimed at valorising fish oil by investing its effects on dyslipidemia. Twenty female rats divided in four groups: Group 1 was fed with standard laboratory diet (SLD); while groups 2, 3 and 4 received the SLD supplemented with cooked egg yolk (5 g/day/rat). After 16 weeks, group 3 received only the SLD and group 4 was fed with SLD supplemented with E. fimbriata oil (1 g/day/kg of body mass) during 3 weeks. At the end of the test, animals were kill and some organs were removed. Some blood biochemical parameters were also measured. Result showed that the hyperlidemic diet induced weight gain, tissular and plasma disorders characterized by increase of cholesterol, triglycerides, LDL Cholesterol and decrease of HDL Cholesterol indicating mixed dyslipidemia in group 2 compare to others groups. Group 4 had a significantly (p˂0.05) decrease in cholesterolemia, triglyceridemia, CLDL and increase levels of CHDL. There was also a tendency for disappearance in tissues disorders. E.fimbriata oil has hypolipidemic effects and could be used to prevent cardiovascular risks. This study should continue with determination of fatty acid composition of this fish oil.Keywords: Overweight, lipid, dyslipidemia, hyperlipidemia, hypolipidemia

The Effect of High-Fat Diet-Induced Obesity on the Expression of Nutrient Chemosensors in the Mouse Stomach and the Gastric Ghrelin Cell

The stomach is the primary source of the orexigenic and adiposity-promoting hormone, ghrelin. There is emerging evidence on the nutrient-mediated modulation of gastric ghrelin secretion. However, limited information is available on gastric nutrient-sensing mechanisms in high-fat diet (HFD)-induced obesity. This study investigated the impact of HFD-induced obesity on the expression of nutrient chemosensors in mouse stomach, particularly ghrelin cells. Male C57BL/6 mice were fed either a standard laboratory diet (SLD) or HFD for 12 weeks. The expression of ghrelin, enzymes involved in ghrelin production (PC1/3, GOAT) and nutrient chemosensors (CD36, FFAR2&4, GPR93, CaSR, mGluR4 and T1R3) was determined by quantitative RT-PCR in the mouse corpus and antrum. Immunohistochemistry assessed the protein expression of CaSR and ghrelin in the corpus and antrum. Antral mRNA levels of CaSR and PC1/3 were increased in HFD compared to SLD mice, while mRNA levels of all other nutrient chemosensors examined remained unchanged. CaSR immunolabelling was observed in the gastric antrum only. Nearly 80% of antral ghrelin cells expressed CaSR, with a similar cell density and co-expression in SLD and HFD mice. In conclusion, HFD-induced obesity increased CaSR mRNA expression in mouse antrum. However, the high antral co-expression of CaSR and ghrelin was unaltered in HFD compared to SLD mice.

Different Forms of Ursolic Acid and Their Effect on Liver Regeneration

The aim of this study was to determine the effect of natural and encapsulated sources of ursolic acid on liver regeneration. Four ursolate sources were tested. Two forms of ursolic acid encapsulates were combined with cyclodextrins, i.e., gamma-CD (gCD) and beta-CD, and two natural sources were adjusted by homogenization (HAP) and micronization of apple peel using Jonagold apples. All ursolate forms were applied intragastrically in daily doses of 20 mg for 7 days. Laboratory rats were fed with standard laboratory diet. Further, gCD and MAP were also tested with a high-fat diet (6 weeks). Partial hepatectomy (PH) was performed 24 hours before the end of the experiment. The concentration of plasma hepatocyte growth factor (HGF) was determined with an immunoassay; simultaneously, the expression of HGF and CYP7A1 in the liver was quantified through qPCR. HGF expression and plasma levels were significantly increased 24 hours after PH in both the HAP (p=0.038) and HFgCD groups (p=0.036), respectively. The correlation between HGF expression and plasma values was significant (p=0.04). The positive effects on liver regeneration were found in both the gCD and HAP forms of ursolic acid, whose effects were confirmed through the upregulation of HGF.

Influence of Diets with Varying Essential/Nonessential Amino Acid Ratios on Mouse Lifespan

An adequate intake of essential (EAA) and non-essential amino acids (NEAA) is crucial to preserve cell integrity and whole-body metabolism. EAA introduced with diet may be insufficient to meet the organismal needs, especially under increased physiological requirements or in pathological conditions, and may condition lifespan. We therefore examined the effects of iso-caloric and providing the same nitrogenous content diets, any diet containing different stoichiometric blends of EAA/NEAA, on mouse lifespan. Three groups of just-weaned male Balb/C mice were fed exclusively with special diets with varying EAA/NEAA ratios, ranging from 100%/0% to 0%/100%. Three additional groups of mice were fed with different diets, two based on casein as alimentary proteins, one providing the said protein, one reproducing the amino acidic composition of casein, and the third one, the control group, was fed by a standard laboratory diet. Mouse lifespan was inversely correlated with the percentage of NEAA introduced with each diet. Either limiting EAA, or exceeding NEAA, induced rapid and permanent structural modifications on muscle and adipose tissue, independently of caloric intake. These changes significantly affected food and water intake, body weight, and lifespan. Dietary intake of varying EAA/NEAA ratios induced changes in several organs and profoundly influenced murine lifespan. The balanced content of EAA provided by dietary proteins should be considered as the preferable means for “optimal” nutrition and the elevated or unbalanced intake of NEAA provided by food proteins may negatively affect the health and lifespan of mice.

A rotating light cycle promotes weight gain and hepatic lipid storage in mice

Processes involved in regulation of energy balance and intermediary metabolism are aligned to the light-dark cycle. Shift-work and high-fat diet (HFD)-induced obesity disrupt circadian rhythmicity and are associated with increased risk of nonalcoholic fatty liver disease. This study aimed to determine the effect of simulating shift work on hepatic lipid accumulation in lean and HFD mice. C57BL/6 mice fed a standard laboratory diet (SLD) or HFD for 4 wk were further allocated to a normal light (NL) cycle (lights on: 0600–1800) or rotating light (RL) cycle [3 days NL and 4 days reversed (lights on: 1800–0600) repeated] for 8 wk. Tissue was collected every 3 h beginning at 0600. HFD mice gained more weight than SLD mice, and RL mice gained more weight than NL mice. SLD-NL and HFD-NL mice, but not RL mice, were more active, had higher respiratory quotients, and consumed/expended more energy during the dark phase compared with the light phase. Blood glucose and plasma cholesterol and triglyceride concentrations were elevated in HFD and SLD-RL compared with SLD-NL mice. Hepatic glycogen was elevated in HFD compared with SLD mice. Hepatic triglycerides were elevated in SLD-RL and HFD mice compared with SLD-NL. Circadian rhythmicity of hepatic acetyl-CoA carboxylase (ACACA) mRNA was phase shifted in SLD-RL and HFD-NL and lost in HFD-RL mice. Hepatic ACACA protein was reduced in SLD-RL and HFD mice compared with SLD-NL mice. Hepatic adipose triglyceride lipase was elevated in HFD-NL compared with SLD-NL but lower in RL mice compared with NL mice irrespective of diet. In conclusion, an RL cycle model of shift work promotes weight gain and hepatic lipid storage even in lean conditions.NEW & NOTEWORTHY In this publication we describe the effects of a rotating light cycle model of shift work in lean and high-fat diet-induced obese mice on body mass, diurnal patterns of energy intake and expenditure, and hepatic lipid storage. The data indicate that modeling shift work, via a rotating light cycle, promotes weight gain and hepatic lipid accumulation even in mice on a standard laboratory diet.