An experimental model of western diet in female Wistar rats leads to cardiac hypoxia related to a stimulated contractility.

Previous studies in Western diet (WD)-fed male rats have highlighted a link between the stimulation of cardiac contractility, mitochondrial adaptations and a pro-inflammatory fatty acid profile of phospholipids in the heart. Our objectives were to determine (1) if WD-fed female Wistar rats and obese humans display a similar pro-inflammatory profile in their cardiac phospholipids and (2) if this lipid profile is associated with deleterious effects on the heart of the female rodents. Female Wistar rats were fed WD for 5 weeks or a laboratory chow as a control. Ionic homeostasis, redox status, inflammation markers, and fatty acid composition of phospholipids were analysed in the heart. WD increased the abdominal fat mass without modifying the body weight of female rats. As previously found in males, a WD induced a shift in membrane fatty acid composition toward a pro-inflammatory profile in the female rats, but not in obese humans. It was associated with an increased COX2 expression suggesting an increased pro-inflammatory eicosanoid production. Signs of increased intracellular calcium strongly supported a stimulation of cardiac contractility without any induction of apoptosis. The heart of WD-fed rats exhibited a hypoxic state as a higher HIF1-α expression was reported. The expressions of antioxidant enzymes were increased, but the redox reserves against reactive oxygen species were lowered. In conclusion, as previously observed in males, we suppose that cardiac abnormalities are magnified with severe obesity in female rats, leading to hypoxia and intense oxidative stress which could ultimately induce cell death and heart failure.

Docosahexaenoic acid and etanercept could reduce functional and metabolic alterations during collagen-induced arthritis in rats without any synergistic effect.

AIMS: Rheumatoid arthritis is an autoimmune disease which induces chronic inflammation and increases the risk for sarcopenia and metabolic abnormalities. Nutritional strategies using omega 3 polyunsaturated fatty acids could be proposed to alleviate inflammation and improve the maintenance of lean mass. Independently, pharmacological agents targeting key molecular regulators of the pathology such as TNF alpha could be proposed, but multiple therapies are frequently necessary increasing the risk for toxicity and adverse effects. The aim of the present study was to explore if the combination of an anti-TNF therapy (Etanercept) with dietary supplementation with omega 3 PUFA could prevent pain and metabolic effects of RA. MATERIALS AND METHODS: RA was induced using collagen-induced arthritis (CIA) in rats to explore of supplementation with docosahexaenoic acid, treatment with etanercept or their association could alleviate symptoms of RA (pain, dysmobility), sarcopenia and metabolic alterations. KEY FINDINGS: We observed that Etanercept had major benefits on pain and RA scoring index. However, DHA could reduce the impact on body composition and metabolic alterations. SIGNIFICANCE: This study revealed for the first time that nutritional supplementation with omega 3 fatty acid could reduce some symptoms of rheumatoid arthritis and be an effective preventive treatment in patients who do not need pharmacological therapy, but no sign of synergy with an anti-TNF agent was observed.

Eccentric and concentric exercises induce different adaptions in adipose tissue biology

Alterations in adipose tissue (AT) metabolism related to inflammation and adipokine’s production lead to perturbations in its capacity to store lipids and release fatty acids (FA) during feeding/fasting transition or during exercise. Exercise has a beneficial effect on AT metabolism, but conventional trainings are not always suitable for patients with functional limitations. Dynamic eccentric (ECC) exercise prevents the accumulation of AT and may then overcome those limitations. Consequently, this study aimed at investigating AT’s adaptations after ECC training. Nine-week-old male rats were randomly assigned to a control sedentary or three-trained groups for which treadmill slopes modulated exercise oxygen consumption (VO2) and mechanical work (n = 15 per group): (1) + 15% uphill-concentric group (CONC), (2) − 15% downhill group (ECC15, same mechanical work as CONC) and (3) − 30% downhill group (ECC30, same VO2, or oxygen cost as CONC). Body composition and energy expenditure (EE) were measured before and after 8 weeks of training. Subcutaneous AT was collected to study total FA profile and gene expression. Higher total EE was driven by lean mass gain in trained animals. In AT, there was a decrease in arachidonic acid with CONC or ECC15 training. Increased adiponectin, leptin, lipases, Glut4 and Igf1 mRNA levels in ECC15 group suggested major metabolic adaption in AT. In conclusion, ECC could induce beneficial modifications in AT fatty acid profile and the expression of key genes related to metabolism and insulin sensitivity. (AU)

Eccentric and concentric exercises induce different adaptions in adipose tissue biology.

Alterations in adipose tissue (AT) metabolism related to inflammation and adipokine's production lead to perturbations in its capacity to store lipids and release fatty acids (FA) during feeding/fasting transition or during exercise. Exercise has a beneficial effect on AT metabolism, but conventional trainings are not always suitable for patients with functional limitations. Dynamic eccentric (ECC) exercise prevents the accumulation of AT and may then overcome those limitations. Consequently, this study aimed at investigating AT's adaptations after ECC training. Nine-week-old male rats were randomly assigned to a control sedentary or three-trained groups for which treadmill slopes modulated exercise oxygen consumption (VO2) and mechanical work (n = 15 per group): (1) + 15% uphill-concentric group (CONC), (2) - 15% downhill group (ECC15, same mechanical work as CONC) and (3) - 30% downhill group (ECC30, same VO2, or oxygen cost as CONC). Body composition and energy expenditure (EE) were measured before and after 8 weeks of training. Subcutaneous AT was collected to study total FA profile and gene expression. Higher total EE was driven by lean mass gain in trained animals. In AT, there was a decrease in arachidonic acid with CONC or ECC15 training. Increased adiponectin, leptin, lipases, Glut4 and Igf1 mRNA levels in ECC15 group suggested major metabolic adaption in AT. In conclusion, ECC could induce beneficial modifications in AT fatty acid profile and the expression of key genes related to metabolism and insulin sensitivity.

Inhibition of the endocannabinoid system reverses obese phenotype in aged mice and partly restores skeletal muscle function.

Sarcopenia, the age-related loss of skeletal muscle mass, is associated with lipid accumulation and anabolic resistance; phenomena also observed in obesity and worsen when obesity and aging are combined. The endocannabinoid system (ECS) is overactivated in obesity, but its role in aging obesity-related muscle dysfunction is unknown. The aims of this study were to evaluate the effect of inhibition of the ECS by rimonabant (RIM) on the metabolic alterations induced by a high-fat high-sucrose diet and on skeletal muscle mass/function in aged mice. Eighteen-month-old male mice were subjected to a control (CTL) or a high-fat high-sucrose (HFHS) diet for 24 weeks. Mice were administered with saline or RIM (10 mg/kg/day) for the last 4 weeks of the diet. Skeletal muscle function was evaluated by open-field, rotarod, and grip strength tests. Metabolic alterations in liver, adipose tissue, and skeletal muscle were investigated by quantitative RT-PCR. Body mass was higher in HFHS mice compared to CTL mice (48.0 ± 1.5 vs. 33.5 ± 0.7 g, P < 0.01), as a result of fat accumulation (34.8 ± 1.0 vs. 16.7 ± 0.8%, P < 0.01). RIM reduced body fat mass in both CTL (-16%, P < 0.05) and HFHS conditions (-40%, P < 0.01), without affecting hindlimb skeletal muscle mass. In HFHS mice, grip strength evolution was improved (-0.29 ± 0.06 vs. -0.49 ± 0.06 g/g lean mass, P < 0.05), and rotarod activity was increased by ≈60% in response to RIM (45.9 ± 6.3 vs. 28.5 ± 4.6 cm, P < 0.05). Lipolysis and ß-oxidation genes were upregulated in the liver as well as genes involved in adipose tissue browning. These results demonstrate that inhibition of the ECS induces metabolic changes in liver and adipose tissue associated with a reversion of the obese phenotype and that RIM is able to improve motor coordination and muscle strength in aged mice, without affecting skeletal muscle mass.NEW & NOTEWORTHY In 24-month-old mice submitted to high-fat high-sucrose-induced obesity, inhibition of the endocannabinoid system by rimonabant reversed the obese phenotype by promoting adipose tissue browning and ß-oxidation in the liver but not in skeletal muscle. These metabolism modifications are associated with improved skeletal muscle function.

A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. (AU)

The effect of camelina oil on vascular function in essential hypertensive patients with metabolic syndrome: a randomized, placebo-controlled, double-blind study.

BACKGROUND: The effects of a dietary supplementation with the vegetable ω-3 α-linolenic acid (ALA) on cardiovascular homeostasis are unclear. In this context, it would be interesting to assess the effects of camelina oil. OBJECTIVE: This study aimed to assess the cardiovascular and metabolic effects of camelina oil in hypertensive patients with metabolic syndrome. METHODS: In a double-blind, placebo-controlled randomized study, treated essential hypertensive patients with metabolic syndrome received, during 6 mo, either cyclodextrin-complexed camelina oil containing ≈ 1.5 g ALA/d (n = 40) or an isocaloric placebo (n = 41), consisting of the same quantity of cyclodextrins and wheat starch. Anthropometric data, plasma lipids, glycemia, insulinemia, creatininemia, TBARs, high-sensitivity C-reactive protein, and n-3, n-6, and n-9 fatty acids in erythrocyte membranes were measured. Peripheral and central blood pressures, arterial stiffness, carotid intima-media thickness, and brachial artery endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent dilatation were assessed. RESULTS: Compared with placebo, camelina oil increased ALA (mean ± SD: 0 ± 0.04 compared with 0.08 ± 0.06%, P <0.001), its elongation product EPA (0 ± 0.5 compared with 0.16 ± 0.65%, P <0.05), and the n-9 gondoic acid (GA; 0 ± 0.04 compared with 0.08 ± 0.04%, P <0.001). No between-group difference was observed for cardiovascular parameters. However, changes in FMD were associated with the magnitude of changes in EPA (r = 0.26, P = 0.03). Compared with placebo, camelina oil increased fasting glycemia (-0.2 ± 0.6 compared with 0.3 ± 0.5 mmol/L, P <0.001) and HOMA-IR index (-0.8 ± 2.5 compared with 0.5 ± 0.9, P <0.01), without affecting plasma lipids, or inflammatory and oxidative stress markers. Changes in HOMA-IR index were correlated with the magnitude of changes in GA (r = 0.32, P <0.01). Nutritional intake remained similar between groups. CONCLUSION: ALA supplementation with camelina oil did not improve vascular function but adversely affected glucose metabolism in hypertensive patients with metabolic syndrome. Whether this adverse effect on insulin sensitivity is related to GA enrichment, remains to be elucidated.

A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles.

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10 weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9 weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3 µg/100 g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. Taken together, these results suggest that a chronic low-dose L-lactate intake has a beneficial health effect on some skeletal muscles and the myocardium through the activation of the NHE1/NCX1 axis, a decrease in cellular calcium and an increase in cellular magnesium. The treatment can be beneficial for the health of young rodents in relation to chronic oxidative stress-related diseases.

Adipose Tissue Dysfunctions in Response to an Obesogenic Diet Are Reduced in Mice after Transgenerational Supplementation with Omega 3 Fatty Acids.

Obesity is characterized by profound alterations in adipose tissue (AT) biology, leading to whole body metabolic disturbances such as insulin resistance and cardiovascular diseases. These alterations are related to the development of a local inflammation, fibrosis, hypertrophy of adipocytes, and dysregulation in energy homeostasis, notably in visceral adipose tissue (VAT). Omega 3 (n-3) fatty acids (FA) have been described to possess beneficial effects against obesity-related disorders, including in the AT; however, the long-term effect across generations remains unknown. The current study was conducted to identify if supplementation with n-3 polyunsaturated FA (PUFA) for three generations could protect from the consequences of an obesogenic diet in VAT. Young mice from the third generation of a lineage receiving a daily supplementation (1% of the diet) with fish oil rich in eicosapentaenoic acid (EPA) or an isocaloric amount of sunflower oil, were fed a high-fat, high-sugar content diet for 4 months. We explore the transcriptomic adaptations in each lineage using DNA microarray in VAT and bioinformatic exploration of biological regulations using online databases. Transgenerational intake of EPA led to a reduced activation of inflammatory processes, perturbation in metabolic homeostasis, cholesterol metabolism, and mitochondrial functions in response to the obesogenic diet as compared to control mice from a control lineage. This suggests that the continuous intake of long chain n-3 PUFA could be preventive in situations of oversupply of energy-dense, nutrient-poor foods.

Transgenerational supplementation with eicosapentaenoic acid reduced the metabolic consequences on the whole body and skeletal muscle in mice receiving an obesogenic diet.

PURPOSE: The effect of manipulating the fatty acid profile of the diet over generations could affect the susceptibility to develop obesity and metabolic disorders. Although some acute effects were described, the impact of transgenerational continuous supplementation with omega 3 fatty acids on metabolic homeostasis and skeletal muscle metabolic flexibility during a nutritional stress is unknown. METHODS: We analyzed the effect of an obesogenic diet in mice after transgenerational supplementation with an omega-3 rich oil (mainly EPA) or a control oil. Young F3 animals received a high fat and high sucrose diet for 4 months. Whole-body biometric data were recorded and lipidomic/transcriptomic adaptations were explored in the skeletal muscle. RESULTS: F3 mice from the lineage supplemented with EPA gained less weight, fat mass, and exhibited better metabolic parameters after the obesogenic diet compared to mice from the control lineage. Transcriptomic exploration of skeletal muscle showed differential regulation of biological processes such as fibrosis, fatty acid catabolism, and inflammation between lineages. These adaptations were associated to subtle lipid remodeling of cellular membranes with an enrichment in phospholipids with omega 3 fatty acid in mice from the EPA lineage. CONCLUSION: Transgenerational and continuous intake of EPA could help to reduce cardiovascular and metabolic risks related to an unbalanced diet by the modulation of insulin sensitivity, fatty acid metabolism, and fibrosis in skeletal muscle.

Deleterious Effect of High-Fat Diet on Skeletal Muscle Performance Is Prevented by High-Protein Intake in Adult Rats but Not in Old Rats.

The phenotype of sarcopenic obesity is frequently associated with impaired muscle strength and performance. Ectopic lipid deposition may interfere with muscle anabolic response especially during aging. Evidence is scarce concerning the potential interplay among aging and nutrient imbalance on skeletal muscle functionality. The objective of the present study was to investigate the impact of protein intake in the context of an obesogenic diet on skeletal muscle functional properties and intramuscular lipid infiltration. Two groups of forty-two adult and thirty-seven old male Wistar rats were randomly divided into four groups: isocaloric standard diet (12% protein, 14% lipid, as ST12); isocaloric standard (high-protein) diet (25% protein, 14% lipid, ST25); hypercaloric high-fat (normal-protein) diet (12% protein, 45% lipid, HF12); and hypercaloric high-fat (high-protein) diet (25% protein, 45% lipid, HF25). The nutritional intervention lasted 10 weeks. Total body composition was measured through Echo-MRI. Lipids were extracted from tibialis anterior muscle and analyzed by gas-liquid chromatography. The functional properties of the plantarflexor muscles were evaluated in vivo on an isokinetic dynamometer. Maximal torque was assessed from the torque-frequency relationship in isometric condition and maximal power was evaluated from the torque-velocity relationship in concentric condition. In adult rats high-protein intake combined with high-fat diet determined a lower decrease in relative isometric torque, normalized to either FFM or body weight, compared with adult rats fed a high-fat normal-protein diet. High-fat diet was also detrimental to relative muscle power, as normalized to body weight, that decreased to a larger extent in adult rats fed a high-fat normal-protein diet than their counterparts fed a normal-fat, high-protein diet. The effect of high-fat diet observed in adults, with the enhanced protein intake (25%) conferring some kind of protection against the negative effects of HFD, may be linked to the reduced intramuscular fat in this group, which may have contributed to preserve, at least partly, the contractile properties. A potential role for high-protein diet in preventing ectopic lipid deposition needs to be explored in future research. Detrimental effects of high- fat diet on skeletal muscle performance are mitigated by high- protein intake in adult rats but not in old rats.

An Integrated Analysis of miRNA and Gene Expression Changes in Response to an Obesogenic Diet to Explore the Impact of Transgenerational Supplementation with Omega 3 Fatty Acids.

Insulin resistance decreases the ability of insulin to inhibit hepatic gluconeogenesis, a key step in the development of metabolic syndrome. Metabolic alterations, fat accumulation, and fibrosis in the liver are closely related and contribute to the progression of comorbidities, such as hypertension, type 2 diabetes, or cancer. Omega 3 (n-3) polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), were identified as potent positive regulators of insulin sensitivity in vitro and in animal models. In the current study, we explored the effects of a transgenerational supplementation with EPA in mice exposed to an obesogenic diet on the regulation of microRNAs (miRNAs) and gene expression in the liver using high-throughput techniques. We implemented a comprehensive molecular systems biology approach, combining statistical tools, such as MicroRNA Master Regulator Analysis pipeline and Boolean modeling to integrate these biochemical processes. We demonstrated that EPA mediated molecular adaptations, leading to the inhibition of miR-34a-5p, a negative regulator of Irs2 as a master regulatory event leading to the inhibition of gluconeogenesis by insulin during the fasting-feeding transition. Omics data integration provided greater biological insight and a better understanding of the relationships between biological variables. Such an approach may be useful for deriving innovative data-driven hypotheses and for the discovery of molecular-biochemical mechanistic links.

EPA is Cardioprotective in Male Rats Subjected to Sepsis, but ALA Is Not Beneficial.

It has been proven that dietary eicosapentaenoic acid (C20:5 n-3 or EPA) protects the heart against the deleterious effects of sepsis in female rats. We do not know if this is the case for male rodents. In this case, the efficiency of other n-3 polyunsaturated fatty acids (PUFAs) remains to be determined in both female and male rats. This study aimed at (i) determining whether dietary EPA is cardioprotective in septic male rats; (ii) evaluating the influence of dietary α-linolenic (C18:3 n-3 or ALA) on cardiac function during this pathology; and (iii) finding out the physiological and molecular mechanisms responsible for the observed effects. Sixty male rats were divided into three dietary groups. The animals were fed a diet deficient in n-3 PUFAs (DEF group), a diet enriched with ALA (ALA group) or a diet fortified with EPA (EPA group) for 6 weeks. Thereafter, each group was subdivided into 2 subgroups, one being subjected to cecal ligation and puncture (CLP) and the other undergoing a fictive surgery. Cardiac function was determined in vivo and ex vivo. Several parameters related to the inflammation process and oxidative stress were determined. Finally, the fatty acid compositions of circulating lipids and cardiac phospholipids were evaluated. The results of the ex vivo situation indicated that sepsis triggered cardiac damage in the DEF group. Conversely, the ex vivo data indicated that dietary ALA and EPA were cardioprotective by resolving the inflammation process and decreasing the oxidative stress. However, the measurements of the cardiac function in the in vivo situation modulated these conclusions. Indeed, in the in vivo situation, sepsis deteriorated cardiac mechanical activity in the ALA group. This was suspected to be due to a restricted coronary flow which was related to a lack of cyclooxygenase substrates in membrane phospholipids. Finally, only EPA proved to be beneficial in sepsis. Its action necessitates both resolution of inflammation and increased coronary perfusion. In that sense, dietary ALA, which does not allow the accumulation of vasodilator precursors in membrane lipids, cannot be protective during the pathology.

Metabolomics reveals plausible interactive effects between dairy product consumption and metabolic syndrome in humans.

BACKGROUND & AIMS: Metabolic syndrome (MetS) induces major disturbances in plasma metabolome, reflecting abnormalities of several metabolic pathways. Recent evidences have demonstrated that the consumption of dairy products may protect from MetS, but the mechanisms remains unknown. The present study aimed at identify how the consumption of different types of dairy products could modify the changes in plasma metabolome during MetS. METHODS: In this observational study, we analyzed how the consumption of dairy products could modify the perturbations in the plasma metabolome induced by MetS in a sample of 298 participants (61 with MetS) from the French MONA LISA survey. Metabolomic profiling was analyzed with UPLC-MS/MS. RESULTS: Subjects with MetS exhibited major changes in plasma metabolome. Significant differences in plasma levels of branched chain amino acids, gamma-glutamyl amino acids, and metabolites from arginine and proline metabolism were observed between healthy control and Mets subjects. Plasma levels of many lipid species were increased with MetS (mono- and diacylglycerols, eicosanoids, lysophospholipids and lysoplasmalogens), with corresponding decreases in short chain fatty acids and plasmalogens. The consumption of dairy products, notably with a low fat content (milk and fresh dairy products), altered metabolite profiles in plasma from MetS subjects. Specifically, increasing consumption of dairy products promoted accumulation of plasma C15:0 fatty acid and was inversely associated to some circulating lysophospholipids, sphingolipids, gamma-glutamyl amino acids, leukotriene B4 and lysoplasmalogens. CONCLUSIONS: the consumption of low fat dairy products could mitigate some of the variations induced by MetS.

Dietary EPA Increases Rat Mortality in Diabetes Mellitus, A Phenomenon Which Is Compensated by Green Tea Extract.

: Diabetes is characterized by a high mortality rate which is often associated with heart failure. Green tea and eicosapentaenoic acid (EPA) are known to lessen some of the harmful impacts of diabetes and to exert cardio-protection. The aim of the study was to determine the effects of EPA, green tea extract (GTE), and a combination of both on the cardiac consequences of diabetes mellitus, induced in Wistar rats by injection of a low dose of streptozotocin (33 mg/kg) combined with a high fat diet. Cardiac mechanical function, coronary reactivity, and parameters of oxidative stress, inflammation, and energy metabolism were evaluated. In the context of diabetes, GTE alone limited several diabetes-related symptoms such as inflammation. It also slightly improved coronary reactivity and considerably enhanced lipid metabolism. EPA alone caused the rapid death of the animals, but this effect was negated by the addition of GTE in the diet. EPA and GTE combined enhanced coronary reactivity considerably more than GTE alone. In a context of significant oxidative stress such as during diabetes mellitus, EPA enrichment constitutes a risk factor for animal survival. It is essential to associate it with the antioxidants contained in GTE in order to decrease mortality rate and preserve cardiac function.

Antioxidant and Cardioprotective Effects of EPA on Early Low-Severity Sepsis through UCP3 and SIRT3 Upholding of the Mitochondrial Redox Potential.

Sepsis still causes death, often through cardiac failure and mitochondrial dysfunction. Dietary ω3 polyunsaturated fatty acids are known to protect against cardiac dysfunction and sepsis lethality. This study set out to determine whether early low-severity sepsis alters the cardiac mitochondrial function in animals fed a Western-type diet and whether dietary eicosapentaenoic acid (EPA) administration protects the myocardium against the deleterious effects of sepsis and if so to seek possible mechanisms for its effects. Rats were divided into two groups fed either an ω3 PUFA-deficient diet ("Western diet," DEF group) or an EPA-enriched diet (EPA group) for 5 weeks. Each group was subdivided into two subgroups: sham-operated rats and rats subjected to cecal ligation and puncture (CLP). In vivo cardiac mechanical function was examined, and mitochondria were harvested to determine their functional activity. Oxidative stress was evaluated together with several factors involved in the regulation of reactive oxygen species metabolism. Sepsis had little effect on cardiac mechanical function but strongly depressed mitochondrial function in the DEF group. Conversely, dietary EPA greatly protected the mitochondria through a decreased oxidative stress of the mitochondrial matrix. The latter was probably due to an increased uncoupling protein-3 expression, already seen in the sham-operated animals. CLP rats in the EPA group also displayed increased mitochondrial sirtuin-3 protein expression that could reinforce the upholding of oxidative phosphorylation. Dietary EPA preconditioned the heart against septic damage through several modifications that protect mitochondrial integrity. This preconditioning can explain the cardioprotective effect of dietary EPA during sepsis.

Impact of Eccentric or Concentric Training on Body Composition and Energy Expenditure.

PURPOSE: To compare the effects of 8-wk eccentric (ECC) versus concentric (CON) training using downhill and uphill running in rats on whole body composition, bone mineral density (BMD), and energy expenditure. METHODS: Animals were randomly assigned to one of the following groups: 1) control (CTRL), 2) +15% uphill-running slope (CON), 3) -15% downhill-running slope (ECC15), and 4) -30% downhill-running slope (ECC30). Those programs enabled to achieve conditions of isopower output for CON and ECC15 and of iso-oxygen uptake (V˙O2) for CON and ECC30. Trained rats ran 45 min at 15 m·min five times per week. Total body mass, fat body mass, and lean body mass (LBM) measured through EchoMRI™, and 24-h energy expenditure including basal metabolic rate (BMR) assessed using PhenoMaster/LabMaster™ cage system were obtained before and after training. At sacrifice, the right femur was collected for bone parameters analysis. RESULTS: Although total body mass increased in all groups over the 8-wk period, almost no change occurred for fat body mass in exercised groups (CON, -4.8 ± 6.18 g; ECC15, 0.6 ± 3.32 g; ECC30, 2.6 ± 6.01 g). The gain in LBM was mainly seen for ECC15 (88.9 ± 6.85 g) and ECC30 (101.6 ± 11.07 g). ECC was also seen to positively affect BMD. An increase in BMR from baseline was seen in exercise groups (CON, 13.9 ± 4.13 kJ·d; ECC15, 11.6 ± 5.10 kJ·d; ECC30, 18.3 ± 4.33 kJ·d) but not in CTRL one. This difference disappeared when BMR was normalized for LBM. CONCLUSIONS: Results indicate that for iso-V˙O2 training, the impact on LBM and BMD is enhanced with ECC as compared with CON, and that for isopower but lower V˙O2 ECC, an important stimulus for adaptation is still observed. This provides further insights for the use of ECC in populations with cardiorespiratory exercise limitations.

Modulation of Insulin Resistance and the Adipocyte-Skeletal Muscle Cell Cross-Talk by LCn-3PUFA.

The cross-talk between skeletal muscle and adipose tissue is involved in the development of insulin resistance (IR) in skeletal muscle, leading to the decrease in the anabolic effect of insulin. We investigated if the long chain polyunsaturated n-3 fatty acids (LCn-3PUFA), eicosapentaenoic and docosapentaenoic acids (EPA and DPA, respectively) could (1) regulate the development of IR in 3T3-L1 adipocytes and C2C12 muscle cells and (2) inhibit IR in muscle cells exposed to conditioned media (CM) from insulin-resistant adipocytes. Chronic insulin (CI) treatment of adipocytes and palmitic acid (PAL) exposure of myotubes were used to induce IR in the presence, or not, of LCn-3PUFA. EPA (50 µM) and DPA (10 µM) improved PAL-induced IR in myotubes, but had only a partial effect in adipocytes. CM from adipocytes exposed to CI induced IR in C2C12 myotubes. Although DPA increased the mRNA levels of genes involved in fatty acid (FA) beta-oxidation and insulin signaling in adipocytes, it was not sufficient to reduce the secretion of inflammatory cytokines and prevent the induction of IR in myotubes exposed to adipocyte's CM. Treatment with DPA was able to increase the release of adiponectin by adipocytes into CM. In conclusion, DPA is able to protect myotubes from PAL-induced IR, but not from IR induced by CM from adipocytes.

Dietary canolol protects the heart against the deleterious effects induced by the association of rapeseed oil, vitamin E and coenzyme Q10 in the context of a high-fat diet.

BACKGROUND: Obesity progressively leads to cardiac failure. Omega-3 polyunsaturated fatty acids (PUFA) have been shown to have cardio-protective effects in numerous pathological situations. It is not known whether rapeseed oil, which contains α-linolenic acid (ALA), has a similar protective effect. Omega-3 PUFAs are sensitive to attack by reactive oxygen species (ROS), and lipid peroxidation products could damage cardiac cells. We thus tested whether dietary refined rapeseed oil (RSO) associated with or without different antioxidants (vitamin E, coenzyme Q10 and canolol) is cardio-protective in a situation of abdominal obesity. METHODS: Sixty male Wistar rats were subdivided into 5 groups. Each group was fed a specific diet for 11 weeks: a low-fat diet (3% of lipids, C diet) with compositionally-balanced PUFAs; a high-fat diet rich in palm oil (30% of lipids, PS diet); the PS diet in which 40% of lipids were replaced by RSO (R diet); the R diet supplemented with coenzyme Q10 (CoQ10) and vitamin E (RTC diet); and the RTC diet supplemented with canolol (RTCC diet). At the end of the diet period, the rats were sacrificed and the heart was collected and immediately frozen. Fatty acid composition of cardiac phospholipids was then determined. Several features of cardiac function (fibrosis, inflammation, oxidative stress, apoptosis, metabolism, mitochondrial biogenesis) were also estimated. RESULTS: Abdominal obesity reduced cardiac oxidative stress and apoptosis rate by increasing the proportion of arachidonic acid (AA) in membrane phospholipids. Dietary RSO had the same effect, though it normalized the proportion of AA. Adding vitamin E and CoQ10 in the RSO-rich high fat diet had a deleterious effect, increasing fibrosis by increasing angiotensin-2 receptor-1b (Ag2R-1b) mRNA expression. Overexpression of these receptors triggers coronary vasoconstriction, which probably induced ischemia. Canolol supplementation counteracted this deleterious effect by reducing coronary vasoconstriction. CONCLUSION: Canolol was found to counteract the fibrotic effects of vitamin E + CoQ10 on cardiac fibrosis in the context of a high-fat diet enriched with RSO. This effect occurred through a restoration of cardiac Ag2R-1b mRNA expression and decreased ischemia.

Early sepsis does not stimulate reactive oxygen species production and does not reduce cardiac function despite an increased inflammation status.

If it is sustained for several days, sepsis can trigger severe abnormalities of cardiac function which leads to death in 50% of cases. This probably occurs through activation of toll-like receptor-9 by bacterial lipopolysaccharides and overproduction of proinflammatory cytokines such as TNF-α and IL-1ß In contrast, early sepsis is characterized by the development of tachycardia. This study aimed at determining the early changes in the cardiac function during sepsis and at finding the mechanism responsible for the observed changes. Sixty male Wistar rats were randomly assigned to two groups, the first one being made septic by cecal ligation and puncture (sepsis group) and the second one being subjected to the same surgery without cecal ligation and puncture (sham-operated group). The cardiac function was assessed in vivo and ex vivo in standard conditions. Several parameters involved in the oxidative stress and inflammation were determined in the plasma and heart. As evidenced by the plasma level of TNF-α and gene expression of IL-1ß and TNF-α in the heart, inflammation was developed in the sepsis group. The cardiac function was also slightly stimulated by sepsis in the in vivo and ex vivo situations. This was associated with unchanged levels of oxidative stress, but several parameters indicated a lower cardiac production of reactive oxygen species in the septic group. In conclusion, despite the development of inflammation, early sepsis did not increase reactive oxygen species production and did not reduce myocardial function. The depressant effect of TNF-α and IL-1ß on the cardiac function is known to occur at very high concentrations. The influence of low- to moderate-grade inflammation on the myocardial mechanical behavior must thus be revisited.