Why and How Meet n-3 PUFA Dietary Recommendations?

Obesity and the metabolic syndrome are systemic inflammatory diseases reaching epidemic proportions. Contemporary changes in human nutrition occurred characterized by increased consumption of fat and of vegetable oils rich in n-6 polyunsaturated fatty acids (PUFAs) together with decrease in n-3 PUFA-rich foods, resulting in an n-6/n-3 ratio of 10–20/1 in Western diet for a ratio around 1/1 in the diet of our ancestors. The literature provides compelling evidence for the health benefit of n-3 PUFA consumption on inflammation and metabolic syndrome prevention and treatment. Such evidence led to the establishment of comprehensive recommendations. However, we show here that, both in collective catering proposed to children and in hospital diet, it is not straightforward to meet such recommendations. Willingness of governments to institute changes, with accountable decisions on catering, nutritional education, and food processing, is required to face our neglected responsibility in promoting balanced diet and consumption of foods rich in essential nutrients in the general population

Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin resistant high-fat diet fed foz/foz mice

Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a ‘pathological’ response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis

Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice

Abstract Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD)

Effects of supplemented isoenergetic diets varying in cereal fiber and protein content on the bile acid metabolic signature and relation to insulin resistance

Bile acids (BA) are potent metabolic regulators influenced by diet. We studied effects of isoenergetic increases in the dietary protein and cereal-fiber contents on circulating BA and insulin resistance (IR) in overweight and obese adults. Randomized controlled nutritional intervention (18 weeks) in 72 non-diabetic participants (overweight/obese: 29/43) with at least one further metabolic risk factor. Participants were group-matched and allocated to four isoenergetic supplemented diets: control; high cereal fiber (HCF); high-protein (HP); or moderately increased cereal fiber and protein (MIX). Whole-body IR and insulin-mediated suppression of hepatic endogenous glucose production were measured using euglycaemic–hyperinsulinemic clamps with [6-62H2] glucose infusion. Circulating BA, metabolic biomarkers, and IR were measured at 0, 6, and 18 weeks. Under isoenergetic conditions, HP-intake worsened IR in obese participants after 6 weeks (M-value: 3.77 ± 0.58 vs. 3.07 ± 0.44 mg/kg/min, p = 0.038), with partial improvement back to baseline levels after 18 weeks (3.25 ± 0.45 mg/kg/min, p = 0.089). No deleterious effects of HP-intake on IR were observed in overweight participants. HCF-diet improved IR in overweight participants after 6 weeks (M-value 4.25 ± 0.35 vs. 4.81 ± 0.31 mg/kg/min, p = 0.016), but did not influence IR in obese participants. Control and MIX diets did not influence IR. HP-induced, but not HCF-induced changes in IR strongly correlated with changes of BA profiles. MIX-diet significantly increased most BA at 18 weeks in obese, but not in overweight participants. BA remained unchanged in controls. Pooled BA concentrations correlated with fasting fibroblast growth factor-19 (FGF-19) plasma levels (r = 0.37; p = 0.003). Higher milk protein intake was the only significant dietary predictor for raised total and primary BA in regression analyses (total BA, p = 0.017; primary BA, p = 0.011). Combined increased intake of dietary protein and cereal fibers markedly increased serum BA concentrations in obese, but not in overweight participants. Possible mechanisms explaining this effect may include compensatory increases of the BA pool in the insulin resistant, obese state; or defective BA transport

Recherche de déterminants génétiques des phénotypes associés au syndrome métabolique en population

The concept of metabolic syndrome corresponds to a non fortuite clustering in an individual of abdominal obesity, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia (low HDL-cholesterol levels) and arterial hypertension. Detecting individuals with a metabolic syndrome allows the discovery of individuals with a high risk of developing cardiovascular diseases. The metabolic syndrome is a complex and multifactorial disorder as its origin is due to the interaction between genetic susceptibility and environmental factors. In the search for genetic factors that predispose to metabolic syndrome phenotypes, we were interested in the common genetic variability of the LXR (liver X receptor) nuclear receptors and the ANGPTLs (angiopoietin-like proteins) family of plasma-borne proteins in either adult (MONICA) or adolescent (HELENA) population-based studies (n=1200 each). We found a consistent association between the LXRalpha rs11039155 polymorphism and a 30% lower risk of metabolic syndrome in the MONICA Lille and Toulouse samples. Moreover, this polymorphism is associated with a higher plasma HDL-cholesterol concentrations (Legry et al 2008). We did not detect a significant influence on LXRalpha and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages. However, the impact of this polymorphism on HDL-cholestérol concentrations have been confirmed in the HELEAN study. Regarding the LXRbeta gene, rs17373080 was consistently associated with a higher risk of obesity (+26%) in MONICA Lille and Toulouse as well as in the HELENA studies (+59%). Functional studies (transfection assays) suggest that this polymorphism may modulate LXRbeta gene expression in vitro. We investigated the common genetic variability of the ANGPTL3, 4 and 6 genes, that are involved in the regulation of energy metabolism. The ANGPTL3 rs11207997 polymorphism was associated with lower plasma HDL cholesterol and ApoA1 levels in both HELENA and MONICA Lille studies. Moreover, the ANGPTL4 rs4076317 polymorphism was associated with a adiposity in MONICA Lille and HELENA studies. We evaluated the frequency of 17 ANGPTL6 SNPs in 100 randomly selected subjects and showed that four SNPs (rs6511435, rs8112063, rs11671983 and rs15723) covered more than 95% of ANGPTL6's known genetic variability. We observed that the G allele of rs8112063 was associated with lower plasma glucose levels in the combined MONICA Lille, Toulouse and Strasbourg study. Moreover, subjects carrying the G allele of rs6511435 tended to have a 20% higher risk of metabolic syndrome compared with AA subjects (Legry et al 2009, in press). Last, we confirmed the impact of the FTO (fat-mass and obesity-associated) rs9939609 polymorphism on the risk of obesity (+29%) and type 2 diabetes (+45%) in the MONICA Lille, Toulouse et Strasbourg studies (Legry et al, sous presse). To conclude, these results suggest that the genetic variability of the LXRs and ANGPTLs genes modulate the determination of the glucose and lipid profiles and the fat mass as well as the risk of metabolic syndrome in humansLe concept de syndrome métabolique correspond à une association non fortuite chez un individu d'une obésité abdominale, d'une hyperglycémie, d'une hypertriglycéridémie, d'une hypoalphalipoproteinémie (faible taux de HDL-cholestérol) et d'une hypertension artérielle. La détection de sujets présentant ce syndrome permet d'identifier des individus à haut risque cardiovasculaire. Le syndrome métabolique est un désordre complexe et multifactoriel dont l'origine est due à l'interaction entre facteurs génétiques et environnementaux. Dans le but d'identifier de nouveaux facteurs de susceptibilité génétique aux phénotypes du syndrome métabolique, nous nous sommes intéressés à la variabilité génétique commune des gènes codant les récepteurs nucléaires LXRs (liver X receptor) ainsi qu'à la famille de protéines plasmatiques ANGPTLs (angiopoietin-like proteins) dans des études de population d'adultes (MONICA) et d'adolescents (HELENA) (n=1200 chacune). Nous avons mis en évidence une association entre le polymorphisme rs11039155 du gène codant LXRalpha et une diminution de 30% du risque de syndrome métabolique dans les échantillons MONICA Lille et Toulouse. De plus, ce polymorphisme est associé à une augmentation de la concentration plasmatique en HDL-cholestérol (Legry et al 2008). Nous n'avons pas détecté d'impact significatif de ce polymorphisme sur l'expression du gène codant LXRa ou de son gène cible ATP-binding cassette transporter A1 (ABCA1) dans des cultures primaires de macrophages humains. Cependant, l'impact de ce polymorphisme sur la concentration plasmatique en HDL-cholestérol a été confirmé dans l'étude HELENA. Concernant le gène codant LXRbeta, le polymorphisme rs17373080 est associé à une augmentation de 26% du risque d'obésité dans les études MONICA Lille et Toulouse et de 59% du risque de surpoids dans HELENA. Des études fonctionnelles de transfection cellulaire suggèrent que ce polymorphisme pourrait moduler l'expression de LXRbeta in vitro. Nous avons également étudié la variabilité génétique commune de ANGPTL3, 4 et 6, protéines impliquées dans la régulation du métabolisme énergétique. Le polymorphisme rs11207997 de ANGPTL3 est associé à une diminution des taux de HDL-cholestérol et d'ApoA1 dans les études MONICA Lille et HELENA. Par ailleurs, le polymorphisme rs4076317 de ANGPTL4 est associé à une augmentation de l'adiposité dans les études MONICA Lille et HELENA (Legry et al, soumis). De plus, nous avons analysé la variabilité génétique de ANGPTL6. Après avoir évalué la fréquence de 17 polymorphismes génétiques dans une centaine d'individus pris au hasard, nous avons montré que 4 polymorphismes (rs6511435, rs8112063, rs11671983 et rs15723) couvrent plus de 95% de la variabilité génétique connue de ANGPTL6. Le polymorphisme rs8112063 est associé à une diminution de la glycémie dans les études MONICA Lille, Toulouse et Strasbourg combinées. De plus, le polymorphisme rs6511435 est associé à une légère augmentation (20%) du risque de syndrome métabolique dans ces populations (Legry et al 2009, sous presse). Enfin, nous avons confirmé l'impact du polymorphisme rs9939609 du gène FTO (fat-mass and obesity-associated) sur le risque d'obésité (+29%) et de diabète de type 2 (+45%) dans les études MONICA Lille, Toulouse et Strasbourg (Legry et al, sous presse). En conclusion, ces résultats suggèrent un impact non négligeable de la variabilité génétique des gènes codant les LXRs et les ANGPTLs dans la détermination du profil gluco-lipidique et de la masse grasse ainsi que le risque de syndrome métabolique chez l'Homm

Recherche de déterminants génétiques des phénotypes associés au syndrome métabolique en population

Le concept de syndrome métabolique correspond à une association non fortuite chez un individu d'une obésité abdominale, d'une hyperglycémie, d'une hypertriglycéridémie, d'une hypoalphalipoproteinémie (faible taux de HDL-cholestérol) et d'une hypertension artérielle. La détection de sujets présentant ce syndrome permet d'identifier des individus à haut risque cardiovasculaire. Le syndrome métabolique est un désordre complexe et multifactoriel dont l'origine est due à l'interaction entre facteurs génétiques et environnementaux. Dans le but d'identifier de nouveaux facteurs de susceptibilité génétique aux phénotypes du syndrome métabolique, nous nous sommes intéressés à la variabilité génétique commune des gènes codant les récepteurs nucléaires LXRs (liver X receptor) ainsi qu'à la famille de protéines plasmatiques ANGPTLs (angiopoietin-like proteins) dans des études de population d'adultes (MONICA) et d'adolescents (HELENA) (n=1200 chacune). Nous avons mis en évidence une association entre le polymorphisme rs11039155 du gène codant LXRalpha et une diminution de 30% du risque de syndrome métabolique dans les échantillons MONICA Lille et Toulouse. De plus, ce polymorphisme est associé à une augmentation de la concentration plasmatique en HDL-cholestérol (Legry et al 2008). Nous n'avons pas détecté d'impact significatif de ce polymorphisme sur l'expression du gène codant LXRa ou de son gène cible ATP-binding cassette transporter A1 (ABCA1) dans des cultures primaires de macrophages humains. Cependant, l'impact de ce polymorphisme sur la concentration plasmatique en HDL-cholestérol a été confirmé dans l'étude HELENA. Concernant le gène codant LXRbeta, le polymorphisme rs17373080 est associé à une augmentation de 26% du risque d'obésité dans les études MONICA Lille et Toulouse et de 59% du risque de surpoids dans HELENA. Des études fonctionnelles de transfection cellulaire suggèrent que ce polymorphisme pourrait moduler l'expression de LXRbeta in vitro. Nous avons également étudié la variabilité génétique commune de ANGPTL3, 4 et 6, protéines impliquées dans la régulation du métabolisme énergétique. Le polymorphisme rs11207997 de ANGPTL3 est associé à une diminution des taux de HDL-cholestérol et d'ApoA1 dans les études MONICA Lille et HELENA. Par ailleurs, le polymorphisme rs4076317 de ANGPTL4 est associé à une augmentation de l'adiposité dans les études MONICA Lille et HELENA (Legry et al, soumis). De plus, nous avons analysé la variabilité génétique de ANGPTL6. Après avoir évalué la fréquence de 17 polymorphismes génétiques dans une centaine d'individus pris au hasard, nous avons montré que 4 polymorphismes (rs6511435, rs8112063, rs11671983 et rs15723) couvrent plus de 95% de la variabilité génétique connue de ANGPTL6. Le polymorphisme rs8112063 est associé à une diminution de la glycémie dans les études MONICA Lille, Toulouse et Strasbourg combinées. De plus, le polymorphisme rs6511435 est associé à une légère augmentation (20%) du risque de syndrome métabolique dans ces populations (Legry et al 2009, sous presse). Enfin, nous avons confirmé l'impact du polymorphisme rs9939609 du gène FTO (fat-mass and obesity-associated) sur le risque d'obésité (+29%) et de diabète de type 2 (+45%) dans les études MONICA Lille, Toulouse et Strasbourg (Legry et al, sous presse). En conclusion, ces résultats suggèrent un impact non négligeable de la variabilité génétique des gènes codant les LXRs et les ANGPTLs dans la détermination du profil gluco-lipidique et de la masse grasse ainsi que le risque de syndrome métabolique chez l'HommeLILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Are n-3 PUFA dietary recommendations met in in-hospital and school catering?

Literature provides compelling evidence for the health benefits of n-3 polyunsaturated fatty acids (PUFA) consumption and low n-6/n-3 ratio, in particular, on inflammation and metabolic syndrome prevention and treatment. Consequently, recommendations were established for adequate n-3 PUFA supplies in the general population. The aim of our study was to evaluate the fatty acid (FA) profile in collective catering in relation to those recommendations

Dietary lipids and NAFLD : suggestions for improved nutrition.

Non-alcoholic fatty liver disease (NAFLD) ranges from steatosis and hepatic insulin resistance to non-alcoholic steatohepatitis (NASH), advanced fibrosis and cirrhosis. NAFLD is now considered as the hepatic manifestation of the metabolic syndrome, and both are triggered by mechanisms including inflammation, lipid overload and oxidative stress in adipose tissue and liver. Despite accumulation of numerous data on NAFLD physiopathology, therapeutic modulation of the pathways involved appear insufficiently efficient or associated with serious adverse effects. The increased prevalence of NAFLD and metabolic syndrome during the last decades was associated with deep modifications of dietary habits, especially increased fat intakes. Recent literature provides clues of increased saturated (SFA) and n-6 polyunsaturated fatty acids (PUFA) as well as reduced n-3 PUFA in the diet of NAFLD and NASH patients. Indeed, strong data support the detrimental role of high SFA and n-6/n-3 ratio as well as low monounsaturated fatty acids (MUFA) and n-3 PUFA on metabolic parameters, which are ameliorated by administration of n-3 PUFA and MUFA. Despite governments and health associations having revised their recommendations for n-3 PUFA intakes upward during the last decade, those are still inferior to levels proved of therapeutic efficiency and are still not reached in the general population. This short review discusses these issues and provides consequent pragmatic suggestions for enhanced dietary measures for prevention of NAFLD and metabolic syndrome in the general population