M. Alligier

Emulsified lipids increase endotoxemia: possible role in early postprandial low-grade inflammation.

Low-grade inflammation is a risk factor for the onset of atherosclerosis. Little is known about the involvement of endotoxin absorption from the gut during the digestion of lipids. In the present study, we first investigated in humans the impact of a mixed meal containing dispersed lipids on postprandial endotoxemia and inflammation. We then investigated the effect of (i) oil emulsification in vivo in rats and (ii) fatty acid amounts in vitro using Caco-2 cells on postprandial endotoxemia. In humans, postprandial endotoxemia increased early after the meal. Moreover, we evidenced that the endotoxin receptor sCD14 increased during digestion and that chylomicrons could contribute to absorbed endotoxin transport. This could explain the significant peak of inflammatory cytokine IL-6 that we observed 2 h after the mixed meal. Interestingly, in rats, the emulsion led to both higher endotoxemia and hypertriglyceridemia than oil and compared to a control saline load. In vitro, incubation of Caco-2 cells with increasing fatty acid concentrations enhanced epithelial absorption of endotoxin. To our knowledge, this is the first study evidencing in healthy humans that, following a mixed meal containing lipids, increased endotoxemia is associated with raised sCD14 and a peak of IL-6. On a repeated basis, this may thus be a triggering cascade for the onset of atherosclerosis. In this respect, optimizing both dietary fat amount and structure could be a possible strategy to limit such low-grade endotoxemia and inflammation by the control of postprandial lipemia.

Subcutaneous Adipose Tissue Remodeling during the Initial Phase of Weight Gain Induced by Overfeeding in Humans

CONTEXT Deciphering the early processes occurring in adipose tissue during weight gain is a major issue for understanding the development of fat mass and obesity. Experimental overfeeding in humans is a unique situation to tackle these events. OBJECTIVE Our aim was to identify the pathways involved in sc adipose tissue remodeling during the initial phase of weight gain. RESEARCH DESIGN AND METHODS Forty-four healthy men were involved in an overfeeding protocol with a lipid-enriched diet (+760 kcal/d) for 2 months. Subcutaneous abdominal adipose tissue biopsies were taken for histology, transcriptomics, and Western blotting in the basal state, after 14 d, and at the end of the protocol. RESULTS Overfeeding significantly increased body weight (+2.5 kg) and fat mass. Reorganization of gene expression patterns occurred in adipose tissue with an up-regulation of numerous genes involved in lipid metabolism and storage, followed by clusters of genes related to angiogenesis and extracellular matrix remodeling. Histological examination showed increased microvascular density and connective tissue deposition after 56 d of overfeeding, with no changes in the number of macrophages or inflammatory cells. Inhibition of the canonical Wnt/β-catenin signaling pathway and induction of the renin-angiotensin system might be implicated in the remodeling of sc adipose tissue. CONCLUSIONS We characterize the coordinated and time-dependent processes that occur in human adipose tissue during the early phase of weight gain in healthy subjects and identify pathways representing potential targets in pathologies of adipose development, including obesity.

Visceral Fat Accumulation During Lipid Overfeeding Is Related to Subcutaneous Adipose Tissue Characteristics in Healthy Men

CONTEXT The hypothesis of a limited expansion of sc adipose tissue during weight gain provides an attractive explanation for the reorientation of excess lipids toward ectopic sites, contributing to visceral adipose depots and metabolic syndrome. OBJECTIVE Our objective was to define whether the characteristics of sc adipose tissue influence the partition of lipids toward abdominal fat depots during weight gain in healthy men. RESEARCH DESIGN AND METHODS Forty-one healthy nonobese volunteers performed a 56-day overfeeding protocol (+760 kcal/d). Insulin sensitivity was estimated by euglycemic hyperinsulinemic clamp. Changes in abdominal visceral and sc adipose tissue depots were measured by magnetic resonance imaging. The fate of ingested lipids before and after overfeeding was investigated using a [d31]palmitate test meal, and gene expression was measured by real-time PCR in sc fat biopsies. RESULTS Overfeeding led to a 2.5-kg body weight increase with large interindividual variations in abdominal sc and visceral adipose tissues. There was no relationship between the relative expansions of these 2 depots, but the increase in visceral depot was positively associated with the magnitude of the postprandial exogenous fatty acid release in the circulation during the test meal. The regulation of lipid storage-related genes (DGAT2, SREBP1c, and CIDEA) was defective in the sc fat of the subjects exhibiting the largest accumulation in visceral depot. CONCLUSIONS Characteristics of sc adipose tissue appear therefore to contribute to the development of visceral fat depot, supporting the adipose tissue expandability theory and extending it to early stages of weight gain in nonobese subjects.

Overfeeding increases postprandial endotoxemia in men: Inflammatory outcome may depend on LPS transporters LBP and sCD14

SCOPE Low-grade inflammation is a recognized hallmark of obesity. Endotoxins absorbed after high-fat meals have recently been implicated. Plasma lipopolysaccharides binding protein (LBP) and soluble cluster of differentiation 14 (sCD14) have also been suggested as clinical markers of endotoxemia. In mice, the ratio LBP/sCD14 has been associated with high fat diet induced inflammation. We tested the hypothesis that healthy subjects develop inflammation differently during weight gain according to changes of LBP/sCD14 ratio. METHODS AND RESULTS Eighteen healthy men were overfed during 8 wk (+760 kcal/day). Endotoxemia, sCD14, LBP, and IL-6 were measured before and after overfeeding (OF) at fasting (n = 18) and postprandially (subcohort, n = 8). OF did not modify fasting IL-6 but increased the LBP/sCD14 ratio (P = 0.017). Subjects were categorized into tertiles for LBP/sCD14 ratio variation. Subjects in the highest tertile (+90% LBP/sCD14) increased plasma IL-6 (+26%) versus the lowest tertile due to a decrease of sCD14 associated with high LBP. The postprandial accumulation of endotoxins increased after OF (+160%). However, only four responding subjects presented increased postprandial IL-6 accumulation. CONCLUSION OF increases postprandial endotoxemia but the inflammatory outcome may be modulated by endotoxin handling in plasma. This study supports a new concept whereby inflammation setup during the initial phase of weight gain is linked to the relative variations of LBP and sCD14.

Odd Chain Fatty Acids; New Insights of the Relationship Between the Gut Microbiota, Dietary Intake, Biosynthesis and Glucose Intolerance

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1−/− mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1−/− only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.

Regulation of Energy Metabolism and Mitochondrial Function in Skeletal Muscle During Lipid Overfeeding in Healthy Men

CONTEXT/OBJECTIVE The aim of this study was to evaluate the regulation of the fuel partitioning and energy metabolism in skeletal muscle during lipid overfeeding in healthy men. Design/Participants/Intervention: Thirty-nine healthy volunteers were overfed for 56 days with a high-fat diet (3180 kJ/d). Energy metabolism (indirect calorimetry) was characterized in the fasting state and during a test meal before and at the end of the diet. Skeletal muscle biopsies were taken at day 0 and day 56. MAIN OUTCOME MEASURES Change in gene expression, mitochondrial respiration, nicotinamide adenine dinucleotide (NAD(+)) content, and acetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in skeletal muscle was measured. RESULTS Overfeeding increased body weight (+2.6 kg) and fat mass concomitantly with a shift in the use of substrates as energy fuel toward preferential oxidation of carbohydrates instead of lipids. Changes in lipid metabolic gene expression supported this observation, with a reduction in pyruvate dehydrogenase kinase 4 expression that could be the consequences of decreased NAD(+) concentration and reduced deacetylase activity of the sirtuins, as supported by hyperacetylation of PGC-1α after overfeeding. Interestingly, this reduction of the sirtuin PGC-1α pathway was associated with increased mitochondrial gene expression and higher respiration rate under these conditions. CONCLUSION Adaptation to lipid overfeeding and regulation of fuel partitioning in human muscle appear to rely on a dissociation between the regulatory functions of the sirtuin-PGC-1α pathway on fatty acid oxidation and on mitochondrial regulation. This may facilitate lipid storage during a period of positive energy balance while maintaining mitochondrial functions and oxidative capacities.

Nicotinic Acid Effects on Insulin Sensitivity and Hepatic Lipid Metabolism: An In Vivo to In Vitro Study

Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan(®) on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan(®) (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan(®) treatment with a significant-28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri-glyceride production rate was markedly reduced after Niaspan(®) (-68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5 mg/kg · min, p<0.05) and decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p<0.05) in the Niaspan(®) condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCε. This effect was associated with an increase in diacylglycerol and a decrease in tri-glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan(®) treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes.

Evidence-based practice within nutrition : what are the barriers for improving the evidence and how can they be dealt with?

BackgroundEvidence-based clinical research poses special barriers in the field of nutrition. The present review summarises the main barriers to research in the field of nutrition that are not common to all randomised clinical trials or trials on rare diseases and highlights opportunities for improvements.MethodsSystematic academic literature searches and internal European Clinical Research Infrastructure Network (ECRIN) communications during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project.ResultsMany nutrients occur in multiple forms that differ in biological activity, and several factors can alter their bioavailability which raises barriers to their assessment. These include specific difficulties with blinding procedures, with assessments of dietary intake, and with selecting appropriate outcomes as patient-centred outcomes may occur decennia into the future. The methodologies and regulations for drug trials are, however, applicable to nutrition trials.ConclusionsResearch on clinical nutrition should start by collecting clinical data systematically in databases and registries. Measurable patient-centred outcomes and appropriate study designs are needed. International cooperation and multistakeholder engagement are key for success.

P280 Le surpoids protège-t-il des conséquences délétères induites par la surnutrition ?

Introduction Le but de notre etude est de mettre en evidence les adaptations metaboliques induites par une surnutrition chez des individus sains en surpoids ou minces, notamment les modifications du devenir des lipides satures alimentaires. Patients et Methodes 12 sujets (5 surpoids(S) et 7 minces (M)), âges respectivement de 23 ± 1 vs 29 ± 3 ans (NS), d’IMC de 28,7 ± 0,4 vs 22,1 ± 0,5 kg/m2 (p = 0,0002) ont ete soumis a 56 jours de surnutrition hyperlipidique (+ 760Kcal). Lors de deux journees d’exploration metabolique (avant : J0 et apres : J56 la surnutrition), les modifications de la composition corporelle et celles du metabolisme glucidolipidique ont ete evaluees. Le devenir des lipides alimentaires a ete suivi et quantifier, dans les fractions lipidiques, grâce a l’ingestion d’un repas test contenant un traceur des acides gras (le palmitate per deutere). Resultats Tous les sujets (S et M confondus), ont augmente leur poids de 2,8 ± 0,5 kg (p = 0,0001) et leur masse grasse de 1 187 ± 401g (p = 0,013) sans difference significative entre les S et les M. En revanche la localisation de prise de masse grasse abdominale a ete differente entre les S et les M, les S stockant principalement au niveau sous-cutane (GSC) (p = 0,005), alors que les M, plus au niveau visceral. Suite a l’ingestion du repas test, les cinetiques des parametres glucidiques ont ete identiques avant et apres la surnutrition. En revanche, la concentration des acides gras non esterifies (AGNE) a augmente chez les S. Les oxydations lipidiques ont diminue en postprandial seulement chez les M (p = 0,04). Une correlation positive a ete trouvee entre l’augmentation de l’enrichissement du traceur dans les fractions de VLDL (very low density lipoprotein), AGNE et la prise de masse grasse viscerale. Discussion Le stockage dans le tissu adipeux abdominal parait etre correle au devenir des lipoproteines. Les M et les S presentent un stockage different au niveau abdominal associe a des modifications du metabolisme differentes. Conclusion Les surpoids presenteraient une repartition de la masse grasse abdominale en faveur du GSC qui pourraient ainsi mieux les proteger des consequences deleteres de la surnutrition.