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Obesity and its metabolic complications are characterized by subclinical systemic and tissue inflammation. In rodent models of obesity, inflammation and metabolic impairments are linked with intestinal barrier damage. However, whether intestinal permeability is altered in human obesity remains to be investigated. In a cohort of 122 severely obese and non-obese patients, we analyzed intestinal barrier function combining in vivo and ex vivo investigations. We found tight junction impairments in the jejunal epithelium of obese patients, evidenced by a reduction of occludin and tricellulin. Serum levels of zonulin and LPS binding protein, two markers usually associated with intestinal barrier alterations, were also increased in obese patients. Intestinal permeability per se was assessed in vivo by quantification of urinary lactitol/mannitol (L/M) and measured directly ex vivo on jejunal samples in Ussing chambers. In the fasting condition, L/M ratio and jejunal permeability were not significantly different between obese and non-obese patients, but high jejunal permeability to small molecules (0.4 kDa) was associated with systemic inflammation within the obese cohort. Altogether, these results suggest that intestinal barrier function is subtly compromised in obese patients. We thus tested whether this barrier impairment could be exacerbated by dietary lipids. To this end, we challenged jejunal samples with lipid micelles and showed that a single exposure increased permeability to macromolecules (4 kDa). Jejunal permeability after the lipid load was two-fold higher in obese patients compared to non-obese controls and correlated with systemic and intestinal inflammation. Moreover, lipid-induced permeability was an explicative variable of type 2 diabetes. In conclusion, intestinal barrier defects are present in human severe obesity and exacerbated by a lipid challenge. This paves the way to the development of novel therapeutic approaches to modulate intestinal barrier function or personalize nutrition therapy to decrease lipid-induced jejunal leakage in metabolic diseases. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Scope Enhanced adiposity and metabolic inflammation are major features of obesity associated with altered gut microbiota and intestinal barrier. How these metabolic outcomes can be impacted by milk polar lipids (MPL), naturally containing 25% of sphingomyelin, is investigated in mice fed a mixed high-fat (HF) diet . Methods and results Male C57Bl/6 mice receive a HF-diet devoid of MPL (21% fat, mainly palm oil, in chow), or supplemented with 1.1% or 1.6% of MPL (HF-MPL1; HF-MPL2) via a total-lipid extract from butterserum concentrate for 8 weeks. HF-MPL2 mice gain less weight versus HF (p < 0.01). Diets do not impact plasma markers of inflammation but in the liver, HF-MPL2 tends to decrease hepatic gene expression of macrophage marker F4/80 versus HF-MPL1 (p = 0.06). Colonic crypt depth is the maximum in HF-MPL2 (p < 0.05). In cecal microbiota, HF-MPL1 increases Bifidobacterium animalis versus HF (p < 0.05). HF-MPL2 decreases Lactobacillus reuteri (p < 0.05), which correlates negatively with the fecal loss of milk sphingomyelin-specific fatty acids (p < 0.05). Conclusion In mice fed a mixed HF diet, MPL can limit HF-induced body weight gain and modulate gut physiology and the abundance in microbiota of bacteria of metabolic interest. This supports further exploration of how residual unabsorbed lipids reaching the colon can impact HF-induced metabolic disorders.

International audience; Additives stabilize or improve the organoleptic or functional properties (or both) of many dairy products including whipping cream. Their influence on the metabolic effect of dairy cream is scarcely known. We tested the hypothesis that added emulsifier (lactic acid esters of mono- and diglycerides; MAG/DAG), thickener (carrageenan, CGN), or both, could modify the metabolic effect, notably in the intestine and liver. Nine-week-old male C57Bl/6J mice were fed UHT cream (indirect treatment) mixed with nonlipidic powder (final: 13% milkfat) for 1 or 4 wk. We compared creams (1) without additive (Ctl), (2) with thickener (Th), 0.02% of κ-CGN, and (3) with both thickener and emulsifier, 0.1% of MAG/DAG esters (Th/Em). We analyzed plasma parameters, intestine, and liver. Fasting glycemia, insulinemia, triglyceridemia, nonesterified fatty acids, body weight gain, and liver weight did not differ among groups. After 1 wk, Th/Em had higher expression in the duodenum of some of the genes involved in (1) intestinal lipid absorption and (2) tight junction proteins versus Ctl and Th. After 4 wk, mucus cell number in the small intestine was higher in Th/Em versus Ctl and Th. Genes involved in endoplasmic reticulum (ER) stress in the duodenum were more expressed in Th/Em after 1 wk. After 4 wk, in the colon, a higher expression of ER stress genes was observed for Th versus Th/Em and Ctl. Liver damage score was not altered by additives. Adding both CGN (0.02%) and MAG/DAG esters (0.1%) in dairy cream did not result in deleterious outcomes in mice after 4 wk regarding lipid metabolism, intestinal permeability, and liver disorders. The longer term effect of intestinal ER stress modulation deserves further investigation.

International audience; Although UHT heat treatment is being optimized to improve the stability and functional properties of dairy products, its metabolic effects remain scarcely known. As such, we studied the effect of the type of UHT process on lipid metabolism, intestinal barrier, and inflammation in mice. Nine-week-old male C57Bl/6J mice were fed a diet composed of nonlipidic powder mixed with different UHT dairy creams (final: 13% milkfat) for 1 or 4 wk. All creams contained 0.02% of thickener (carrageenan) and were treated via either (1) classical indirect heating process (Th), (2) indirect process at higher temperature (Th+), or (3) direct process by steam injection (ThD). Plasma, epididymal adipose tissue (EAT), and intestine were analyzed. Multivariate principal component analyses were used to identify differential effects of processes. Th+ differed by a globally higher liver damage score compared with that of the other creams. After 4 wk, the duodenal expression of lipid absorption genes fatty acid binding protein 4 (Fatp4) and microsomal triglycerides transfer protein (Mttp) was lower in the Th+ versus Th group. Expression in the colon of tight junction protein zonula occludens 1 (Zo-1) and of some endoplasmic reticulum stress markers was lower in both Th+ and ThD versus the Th group. In EAT, ThD had lower gene expression of several inflammatory markers after 4 wk. Some differential effects may be related to heat-induced physicochemical changes of creams. The type of cream UHT process differentially affected metabolic parameters in mice after a 4-wk fat-rich diet, partly due to cream structure. Altogether, direct steam injection process induced the lowest early markers of high-fat-induced metabolic inflammation in EAT.

Introduction et but de l’etude Les regimes occidentaux sont impliques dans le developpement des maladies metaboliques, dont la composante inflammatoire peut etre due a une alteration de la barriere intestinale. Les produits laitiers contiennent naturellement la matiere grasse sous forme de globule gras, constitues (i) d’un cœur de triglycerides (98 % des lipides) et (ii) d’une membrane biologique riche en lipides mineurs bioactifs, les lipides polaires (2 % des lipides) incluant de maniere specifique la sphingomyeline (SM, ∼ 25 % des lipides polaires). Les composes alimentaires peuvent affecter la barriere intestinale en influencant l’organisation des proteines des jonctions serrees qui sont impliquees dans les transports paracellulaires entre la lumiere intestinale et la circulation. Notre hypothese est que la matiere grasse laitiere exerce certains de ses effets benefiques par l’intermediaire de la SM, notamment sur l’integrite de la barriere intestinale qui pourraient reduire une inflammation. Nous avons teste in vitro l’hypothese que l’interleurkine-8 (IL-8), impliquee dans la maturation de l’epithelium intestinal [1] , serait un acteur des modifications intestinales en reponse aux lipides polaires laitiers. Materiel et methodes Des cellules Caco-2/TC7 cultivees sur filtre Transwell® (modele d’epithelium intestinal) ont ete incubees avec des micelles mixtes lipidiques enrichies ou non en SM laitiere (0 mM, 0,2 mM et 0,4 mM). L’expression genique des proteines impliquees dans les jonctions serrees (Occludine, claudine et JAM-1, des proteines transmembranaires, et ZO-1, proteine intracellulaire) et la concentration d’IL-8 (au pole apical et basolateral) ont ete etudies ainsi que plusieurs marqueurs inflammatoires. Nous avons dans un deuxieme temps incube les cellules avec l’IL-8 recombinante humaine en apical et/ou en basolateral afin d’observer l’impact sur l’expression genique des proteines de jonctions serrees. Resultats et analyse statistique Apres 24 h d’incubation avec des micelles enrichies avec 0,4 mM de SM, nous avons observe une surexpression de l’occludine (p Conclusion Nos resultats revelent un impact de la SM laitiere sur la modulation de l’expression des proteines des jonctions serrees et de l’IL-8, ainsi que de sa concentration. Apres incubation avec l’IL-8 recombinante, nous avons demontre que les modifications induites par la SM sur les jonctions serrees peuvent etre expliquees au moins en partie par l’action de l’IL-8.

Background: Polar lipid (PL) emulsifiers such as milk PLs (MPLs) may affect digestion and subsequent lipid metabolism, but focused studies on postprandial lipemia are lacking. Objective: We evaluated the impact of MPLs on postprandial lipemia in mice and on lipid digestion in vitro. Methods:Female Swiss mice were gavaged with 150 mL of an oil-in-water emulsion stabilized with 5.7 mg of either MPLs or soybean PLs (SPLs) and killed after 1, 2, or 4 h. Plasma lipids were quantified and in the small intestine, gene expression was analyzed by reverse transcriptase‐quantitative polymerase chain reaction. Emulsions were lipolyzed in vitro using a static human digestion model; triglyceride (TG) disappearance was followed by thin-layer chromatography. Results: In mice, after 1 h, plasma TGs tended to be higher in the MPL group than in the SPL group (141 mg/mL vs. 90 mg/mL; P= 0.07) and nonesterified fatty acids (NEFAs) were significantly higher (64 mg/mL vs. 44 mg/mL; P< 0.05). The opposite was observed after 4 h with lower TGs (21 mg/mL vs. 35 mg/mL; P < 0.01) and NEFAs (20 mg/mL vs. 32 mg/mL; P < 0.01) in the MPL group compared with the SPL group. This was associated at 4 h with a lower gene expression of apolipoprotein B (Apob) and Secretion Associated, Ras related GTPase 1 gene homolog B (Sar1b), in the duodenum of MPL mice compared with SPL mice (P < 0.05). In vitro, during the intestinal phase, TGs were hydrolyzed more in the MPL emulsion than in the SPL emulsion (decremental AUCs were 1750%/min vs. 180%/min; P < 0.01). MPLs enhance lipid intestinal hydrolysis and promote more rapid intestinal lipid absorption and sharper kinetics of lipemia. Conclusions: Postprandial lipemia in mice can be modulated by emulsifying with MPLs compared with SPLs, partly through differences in chylomicron assembly, and TG hydrolysis rate as observed in vitro. MPLs may thereby contribute to the long-term regulation of lipid metabolism. J Nutr 2015;145:1770‐7.

Postprandial hyperlipemia is recognized as a major cardio-metabolic risk factor, recently linked to the co-absorption of pro-inflammatory lipopolysaccharides with dietary lipids. This causes endotoxemia that is involved in the pathophysiology of obesity and insulin resistance, but to date the impact of food formulation is unknown. We tested a novel concept that endotoxin absorption can be modulated by fat emulsified structure in the meal, and potentially differently in obese vs. lean men. In a randomized controlled crossover study, eight normal-weight and eight obese age-matched healthy men ingested two isocaloric, isolipidic breakfasts of identical composition including 40 g of milk fat that was emulsified or unemulsified. Plasma- and chylomicron-endotoxemia and chylomicron-triglycerides were measured during 8 h after breakfast ingestion. After emulsion consumption, parallel to an enhanced chylomicronemia, obese subjects presented an early and sharp increase in chylomicron-endotoxemia at 60 min (P time = 0.02), which was higher than (i) after spread fat in obese subjects (P

International audience; 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.

International audience; Obesity and its related disorders have been associated with the presence in the blood of gut bacteria-derived lipopolysaccharides (LPS). However, the factors underlying this low-grade elevation in plasma LPS, so-called metabolic endotoxemia, are not fully elucidated. We aimed to investigate the effects of Western diet (WD) feeding on intestinal and hepatic LPS handling mechanisms in a rat model of diet-induced obesity (DIO). Rats were fed either a standard chow diet (C) or a Western Diet (WD, 45% fat) for 6 wk. They were either fed ad libitum or pair-fed to match the caloric intake of C rats for the first week, then fed ad libitum for the remaining 5 wk. Six-week WD feeding led to a mild obese phenotype with increased adiposity and elevated serum LPS-binding protein (LBP) levels relative to C rats, irrespective of initial energy intake. Serum LPS was not different between dietary groups but exhibited strong variability. Disrupted ileal mucus secretion and decreased ileal Reg3-γ and -β gene expression along with high ileal permeability to LPS were observed in WD compared with C-fed rats. Ileal and cecal intestinal alkaline phosphatase (IAP) activity as well as Verrucomicrobia and Bifidobacterium cecal levels were increased in WD-fed rats compared with C-fed rats. WD consumption did not impact mRNA levels of LPS-handling hepatic enzymes. Correlation analysis revealed that ileal passage of LPS, IAP activity, Proteobacteria levels and hepatic aoah gene expression correlated with serum LPS and LBP, suggesting that ileal mucosal defense impairment induced by WD feeding contribute to metabolic endotoxemia.

International audience; SCOPE: Enhanced adiposity and metabolic inflammation are major features of obesity that could be impacted by dietary emulsifiers. We investigated in high-fat fed mice the effects of using a new polar lipid (PL) emulsifier from milk (MPL) instead of soybean lecithin (soybean PL [SPL]) on adipose tissue and intestinal mucosa function. METHODS AND RESULTS: Four groups of C57BL6 mice received for 8 wks a low-fat (LF) diet or a high-fat diet devoid of PLs or an high-fat diet including MPL (high-fat-MPL) or SPL (high-fat-SPL). Compared with high-fat diet, high-fat-SPL diet increased white adipose tissue (WAT) mass (p \textless 0.05), with larger adipocytes (p \textless 0.05) and increased expression of tumor necrosis factor alpha, monochemoattractant protein-1, LPS-binding protein, and leptin (p \textless 0.05). This was not observed with high-fat-MPL diet despite similar dietary intakes and increased expression of fatty acid transport protein 4 and microsomal TG transfer protein, involved in lipid absorption, in upper intestine (p \textless 0.05). High-fat-MPL mice had a lower expression in WAT of cluster of differentiation 68, marker of macrophage infiltration, versus high-fat and high-fat-SPL mice (p \textless 0.05), and more goblet cells in the colon (p \textless 0.05). CONCLUSIONS: Unlike SPL, MPL in the high-fat diet did not induce WAT hypertrophy and inflammation but increased colonic goblet cells. This supports further clinical exploration of different sources of dietary emulsifiers in the frame of obesity outbreak.

The low-grade inflammation observed in obesity is a risk factor for cardiovascular diseases and insulin resistance. Among factors triggering such inflammation, recent works revealed the role of bacterial lipopolysaccharides (LPS), so-called endotoxins. LPS are naturally present in the gut via the intestinal microbiota. Recent studies show that they can induce in plasma a metabolic endotoxemia after the consumption of unbalanced hyperlipidic meals. This article reviews recent knowledge gained on the role of intestinal lipid absorption and the composition of dietary lipids on: (i) the induction of metabolic endotoxemia, (ii) the types of plasma transporters of LPS and (iii) associated low-grade inflammation. Notably, lipids are present in foods under various physicochemical structures and notably in emulsified form. Our recent works reveal that such structure and the type of emulsifier can modulate postprandial lipemia; recent results on the possible consequences on metabolic endotoxemia will be discussed.

International audience; Endoplasmic reticulum (ER) stress is proposed as a novel link between elevated fatty acids levels, obesity and insulin resistance in liver and adipose tissue. However, it is unknown whether ER stress also contributes to lipid-induced insulin resistance in skeletal muscle, the major tissue responsible of insulin-stimulated glucose disposal. Here, we investigated the possible role of ER stress in palmitate-induced alterations of insulin action, both in vivo, in gastrocnemius of high-palm diet fed mice, and in vitro, in palmitate-treated C(2)C(12) myotubes. We demonstrated that 8 weeks of high-palm diet increased the expression of ER stress markers in muscle of mice, whereas ex-vivo insulin-stimulated PKB phosphorylation was not altered in this tissue. In addition, exposure of C(2)C(12) myotubes to either tuncamycine or palmitate induced ER stress and altered insulin-stimulated PKB phosphorylation. However, alleviation of ER stress by either TUDCA or 4-PBA treatments, or by overexpressing Grp78, did not restore palmitate-induced reduction of insulin-stimulated PKB phosphorylation in C(2)C(12) myotubes. This work highlights that, even ER stress is associated with palmitate-induced alterations of insulin signaling, ER stress is likely not the major culprit of this effect in myotubes, suggesting that the previously proposed link between ER stress and insulin resistance is less important in skeletal muscle than in adipose tissue and liver.

Introduction et but de l’etude La presence dans le sang de lipopolysaccharides (LPS) ou endotoxemie metabolique, liee a une alteration de la barriere intestinale, est impliquee dans le developpement de l’inflammation chronique de bas-grade caracteristique de l’obesite. La consommation d’un regime de type occidental riche en lipides et pauvre en fibres induit une augmentation des taux de LPS circulant mais aussi une hyperphagie transitoire. L’objectif de notre etude etait d’evaluer le role de l’hyperphagie liee a la consommation d’un tel regime dans la cinetique d’alteration des mecanismes regulant la translocation caecale et ileale du LPS. Materiel et methodes Vingt-quatre rats mâles Wistar ont ete nourris avec un regime standard (C) ou un regime Western ad libitum (WD al ) riche en lipides (45 % de l’energie) et appauvri en fibre durant 1 ou 6 semaines. Un troisieme groupe a ete nourri avec l’aliment Western mais avec un apport calorique au meme niveau que les animaux temoins ( pair-feeding , WD pf , n = 12). A l’euthanasie, le passage ileal et caecal de LPS a ete mesure en chambres d’Ussing. L’endotoxemie a ete evaluee par dosage LAL, l’activite de la phosphatase alcaline intestinale (IAP) par dosage colorimetrique et l’expression de molecules impliquees dans la signalisation du LPS ( tlr4, md2, myd88 ) par PCR. Resultats et analyse statistique L’adiposite a 6 semaines etait augmentee chez les animaux nourris avec le regime WD, ad libitum ou non (+81 % et +64 % par rapport a C). Les animaux WD pf presentaient la meme augmentation transitoire de l’activite de l’IAP caecale a 1 semaine que les animaux WD al (+408 % WD pf par rapport a C et +1 052 % WD al par rapport a C). En revanche, alors que les rats WD al presentaient une augmentation transitoire du passage caecal du LPS a 1 semaine (+49 % par rapport a C), celui-ci restait eleve a 6 semaines chez les animaux WD pf (+49 % a 1 et +71 % a 6 semaines par rapport a C). L’expression de md2 a 1 et 6 semaines et de myd88 a 6 semaines etait diminuee chez les rats WD pf (−80, −30 et −41 % par rapport a C, respectivement) contrairement aux rats WD al qui ne presentaient une diminution de md2 (−70 % par rapport a C) qu’a 1 semaine. Dans l’ileon, les animaux WD pf presentaient le meme profil a 1 et 6 semaines que les animaux WD al concernant l’activite de l’IAP (+537 et +329 % WD pf par rapport a C ; +1 000 et +900 % WD al par rapport a C) et l’expression de md2 (−28 et −30 % WD pf par rapport a C ; −31 et −25 %, WD al par rapport a C). Cependant et contrairement aux rats WD al , les animaux WD pf ne presentaient pas de diminution de l’expression de tlr4 mais une diminution de myd88 a 6 semaines (−31 % WD pf par rapport a C). Comme dans le caecum, les animaux WD pf presentaient une augmentation du passage ileal de LPS a 1 et 6 semaines (+81 et +140 % par rapport a C) non observee chez les animaux WD al . Enfin, a 6 semaines, l’endotoxemie etait elevee uniquement chez les animaux WD pf (+1 124 % WD pf par rapport a C). Conclusion Un regime obesogene induit des alterations des mecanismes homeostatiques controlant le passage intestinal du LPS dependantes de la duree de regime et du site intestinal considere ainsi que de l’hyperphagie initiale au moment du changement de regime.

International audience; CONTEXT: Postprandial endotoxemia is a metabolic risk factor, which has been shown to originate from the intestinal absorption of gut lipopolysaccharides (LPS) using nonphysiological high-fat tests. OBJECTIVE: This study aimed to determine whether different realistic fat amounts can modulate postprandial dynamics and handling of LPS by varying postprandial lipidemia in humans of different body mass indices. DESIGN, SETTING, AND PARTICIPANTS: In a randomized, controlled, cross-over study in nutrition research center, eight normal-weight (NW) and eight obese age-matched men, without diabetes nor dyslipidemia, ingested breakfasts containing 10 vs 40 g fat. Blood samples, leukocytes, and chylomicron-rich fractions were obtained during 8 h. Plasma and chylomicron-endotoxemia, plasma LPS transporters (LBP, sCD14) and IL-6, nuclear factor kappaB (NF-kappaB) translocation, and IL-6 gene expression of immune cells were measured. MAIN OUTCOME: The postprandial fatty acid handling after ingesting 40 g fat was previously published as primary outcome. The secondary outcomes were inflammatory ones including postprandial endotoxemia, LPS handling, and plasma markers of inflammation after ingesting 10 or 40 g fat. RESULTS: Chylomicronemia increased in all subjects according to ingested fat amount (P \textless .01), but only obese had higher postprandial endotoxemia after 40 g (P \textless .05). Obese subject chylomicrons were more enriched with LPS compared with NW (PBMI \textless .01). We observed neither NF-kappaB translocation, nor variation of IL-6 expression in leukocytes. In both groups, fat amount did not modify postprandial response of plasma IL-6. However, the area under the curve (AUC) of IL-6 in obese was higher than in NW (P \textless .05) parallel to higher fasting LPS-binding protein (LBP; P \textless .05). AUC of IL-6 was correlated with LBP (P \textless .01). CONCLUSION: Postprandial endotoxemia is modulated by ingested fat amount in obese men. LPS handling in plasma through chylomicrons and LBP seems critical in driving the acute inflammatory response. The pathophysiological importance of repeated postprandial endotoxemia excursions and their contribution to a vicious cycle of LBP-driven low-grade inflammation deserve further investigation in the nutritional management of cardio-metabolic risk prevention.

International audience; The impacts of high-fat diets (HFDs) on the onset of metabolic endotoxemia and low-grade inflammation are well established in rodent models. However, the dose-effect of dietary lipid intakes on these parameters is not known. We hypothesized that increasing dietary lipid amounts could be linked to parallel increases of endotoxemia, low-grade inflammation, and metabolic and intestinal alterations. Six-week-old male C57BL/6J mice were fed a low-fat diet (LFD, 2.6 wt% of lipids), a moderate HFD (mHFD, 22 wt% of lipids), or a very HFD (vHFD, 45 wt% of lipids) formulated mainly using chow ingredients and milk fat. After 12 weeks, white adipose tissues, liver, intestine, distal colon contents, and plasma were collected. Only vHFD mice significantly increased body weight and fat mass vs LFD mice. This was associated with increases of plasma concentrations of triglycerides, leptin and adiponectin, and liver lipids. No such differences were observed between LFD and mHFD mice. However, mHFD developed metabolic endotoxemia and inflammation, unlike vHFD mice. In turn, vHFD mice showed more goblet cells in all intestine segments vs both other groups and a decrease of Bacteroides-Prevotella in their microbiota vs LFD mice. Finally, mHFD mice colon exhibited a decrease in lactobacilli and in the levels of occludin phosphorylation. Altogether, using complex HFD, no associations were observed between dietary lipid amounts and the magnitude of endotoxemia, inflammation, and physiological alterations developed. These results reveal the impact of the diet composition on intestinal goblet cells and mucus coat, bringing new insights about further consequences on HFD-induced metabolic disorders.

International audience; Rats and mice exhibit a spontaneous attraction for lipids. Such a behavior raises the possibility that an orosensory system is responsible for the detection of dietary lipids. The fatty acid transporter CD36 appears to be a plausible candidate for this function since it has a high affinity for long-chain fatty acids (LCFAs) and is found in lingual papillae in the rat. To explore this hypothesis further, experiments were conducted in rats and in wild-type and CD36-null mice. In mice, RT-PCR experiments with primers specific for candidate lipid-binding proteins revealed that only CD36 expression was restricted to lingual papillae although absent from the palatal papillae. Immunostaining studies showed a distribution of CD36 along the apical side of circumvallate taste bud cells. CD36 gene inactivation fully abolished the preference for LCFA-enriched solutions and solid diet observed in wild-type mice. Furthermore, in rats and wild-type mice with an esophageal ligation, deposition of unsaturated LCFAs onto the tongue led to a rapid and sustained rise in flux and protein content of pancreatobiliary secretions. These findings demonstrate that CD36 is involved in oral LCFA detection and raise the possibility that an alteration in the lingual fat perception may be linked to feeding dysregulation.

International audience; Metabolic diseases such as obesity are characterized by a subclinical inflammatory state that contributes to the development of insulin resistance and atherosclerosis. Recent reports also indicate that (i) there are alterations of the intestinal microbiota in metabolic diseases and (ii) absorption of endogenous endotoxins (namely lipopolysaccharides, LPS) can occur, particularly during the digestion of lipids. The aim of the present review is to highlight recently gained knowledge regarding the links between high fat diets, lipid digestion, intestinal microbiota and metabolic endotoxemia & inflammation.

Dairy products derived from the milk of cows fed in pastures are characterised by higher amounts of conjugated linoleic acid and α-linolenic acid (ALA), and several studies have shown their ability to reduce cardiovascular risk. However, their specific metabolic effects compared with standard dairy in a high-fat diet (HFD) context remain largely unknown; this is what we determined in the present study with a focus on the metabolic and intestinal parameters. The experimental animals were fed for 12 weeks a HFD containing 20 % fat in the form of a pasture dairy cream (PDC) or a standard dairy cream (SDC). Samples of plasma, liver, white adipose tissue, duodenum, jejunum and colon were analysed. The PDC mice, despite a higher food intake, exhibited lower fat mass, plasma and hepatic TAG concentrations, and inflammation in the adipose tissue than the SDC mice. Furthermore, they exhibited a higher expression of hepaticPPARαmRNA and adipose tissue uncoupling protein 2 mRNA, suggesting an enhanced oxidative activity of the tissues. These results might be explained, in part, by the higher amounts of ALA in the PDC diet and in the liver and adipose tissue of the PDC mice. Moreover, the PDC diet was found to increase the proportions of two strategic cell populations involved in the protective function of the intestinal epithelium, namely Paneth and goblet cells in the small intestine and colon, compared with the SDC diet. In conclusion, a PDC HFD leads to improved metabolic outcomes and to a stronger gut barrier compared with a SDC HFD. This may be due, at least in part, to the protective mechanisms induced by specific lipids.

International audience; Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFalpha expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.

Introduction Les maladies metaboliques d'origine nutritionnelle sont caracterisees par un metabolisme des lipides perturbe incluant une hyperlipemie postprandiale. Dans ce contexte, un interet se developpe autour des effets des lipides polaires (LP), agents de texture largement utilises dans l'industrie alimentaire. Nous etudions donc l'impact de LP de differentes sources alimentaires (vegetal vs animal) sur la lipemie postprandiale. Materiels et methodes Des souris ont ete gavees avec 2 types d'emulsions, dont les gouttelettes de matiere grasse etaient recouvertes de LP laitiers ou de LP de soja. Le plasma et l'intestin grele ont ete collectes au cours de la digestion. Des cellules intestinales Caco-2/TC7 ont ete incubees 24 heures avec des micelles lipidiques contenant differents L P, phosphatidylcholine ou sphingomyeline (specifique des LP laitiers) pour analyse des chylomicrons secretes. Resultats Une heure apres gavage, les LP Laitiers induisent des concentrations plasmatiques de triglycerides et d'acides gras libres plus elevees que les LP de soja. L'effet inverse est observe apres 4 heures. Ces lipemies differentes sont associees a une moindre expression genique de proteines impliquees dans la secretion des chylomicrons, dans le duodenum du groupe LP laitiers a 4 heures. Ceci suggere que l'absorption et la metabolisation des lipides dependent du type de LP utilise, notamment via une modulation des genes dans l'enterocyte. In vitro , la presence de sphin-gomyeline dans les micelles induit une secretion plus importante de triglycerides sous la forme de plus petits chylomicrons. Ainsi, les effets observes in vivo sont probablement dus a la teneur elevee des LP laitiers en sphingomyeline. Conclusion Ces resultats suggerent que la qualite des lipides polaires utilises pour stabiliser une emulsion influence le metabolisme postprandial des lipides. Ces nouvelles connaissances pourraient servir a la mise en place de formulations alimentaires optimisees. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

International audience; Mice fed a mixture of CLA containing t10,c12-CLA lose fat mass and develop hyperinsulinemia and hepatic steatosis due to an accumulation of TG and cholesterol. Because cholesterol is the precursor in bile acid (BA) synthesis, we investigated whether t10,c12-CLA alters BA metabolism. In Expt. 1, female C57Bl/6J mice were fed a standard diet for 28 d supplemented with a CLA mixture (1 g/100 g) or not (controls). In Expt. 2, the feeding period was reduced to 4, 6, and 10 d. In Expt. 3, mice were fed a diet supplemented with linoleic acid, c9,t11-CLA, or t10,c12-CLA (0.4 g/100 g) for 28 d. In Expt. 1, the BA pool size was greater in CLA-fed mice than in controls and the entero-hepatic circulation of BA was altered due to greater BA synthesis and ileal reclamation. This resulted from higher hepatic cholesterol 7α-hydroxylase (CYP7A1) and ileal apical sodium BA transporter expressions in CLA-fed mice. Furthermore, hepatic Na+/taurocholate co-transporting polypeptide (NTCP) (−52%) and bile salt export pump (BSEP) (−77%) protein levels were lower in CLA-fed mice than in controls, leading to a greater accumulation of BA in the plasma (+500%); also, the cholesterol saturation index and the concentration of hydrophobic BA in the bile were greater in CLA-fed mice, changes associated with the presence of cholesterol crystals. Expt. 2 suggests that CLA-mediated changes were caused by hyperinsulinemia, which occurred after 6 d of the CLA diet before NTCP and BSEP mRNA downregulation (10 d). Expt. 3 demonstrated that only t10,c12-CLA altered NTCP and BSEP mRNA levels. In conclusion, t10,c12-CLA alters BA homeostasis and increases the risk of cholelithiasis in mice.

International audience; The sense of taste informs the body about the quality of ingested foods. Tastant-mediated signals are generated by a rise in free intracellular calcium levels ([Ca(2+)]i) in the taste bud cells and then are transferred to the gustatory area of brain via connections between the gustatory nerves (chorda tympani and glossopharyngeal nerves) and the nucleus of solitary tract in the brain stem. We have recently shown that lingual CD36 contributes to fat preference and early digestive secretions in the mouse. We show here that 1) the induction of an increase in [Ca(2+)]i by linoleic acid is CD36-dependent in taste receptor cells, 2) the spontaneous preference for or conversely conditioned aversion to linoleic acid requires intact gustatory nerves, and 3) the activation of gustatory neurons in the nucleus of the solitary tract elicited by a linoleic acid deposition on the tongue in wild-type mice cannot be reproduced in CD36-null animals. We conclude that the CD36-mediated perception of long-chain fatty acids involves the gustatory pathway, suggesting that the mouse may have a "taste" for fatty foods. This system would constitute a potential physiological advantage under conditions of food scarcity by leading the mouse to select and absorb fatty foods. However, it might also lead to a risk of obesity and associated diseases in a context of constantly abundant food.

Introduction et but de l’etude Les maladies metaboliques d’origine nutritionnelle telle que l’obesite et le diabete de type 2 sont caracterisees par un metabolisme des lipides perturbe incluant une hyperlipemie postprandiale. Dans ce contexte, un interet croissant s’est developpe recemment autour des effets des lipides polaires (LP), agents de texture largement utilises dans l’industrie alimentaire, notamment sur la regulation du metabolisme des lipides. Notre objectif est d’etudier l’impact de LP de differentes sources alimentaires (vegetal vs animal) sur la digestion des lipides et la lipemie postprandiale. Materiel et methodes Des souris ont ete gavees avec 2 types d’emulsions, dont les gouttelettes de matiere grasse etaient de taille similaire mais recouvertes soit de LP de soja, soit de LP laitiers. Le plasma et l’intestin grele ont ensuite ete collectes au cours de la digestion. Parallelement, ces 2 emulsions ont ete digerees in vitro via un modele de digestion humaine statique (phase gastriques et intestinales de 60 min) base sur l’utilisation de fluides digestifs simules et d’enzymes digestives animales. Resultats et Analyse statistique 1 h apres le gavage, les LP Laitiers induisent des concentrations plasmatiques de triglycerides (TG) et d’acides gras libres plus elevees que les LP de soja. L’effet inverse est observe apres 4 h ( P LPxTemps (P In vitro , en phase intestinale, la cinetique d’hydrolyse des TG de l’emulsion a base de LP laitiers est plus rapide que celle de l’emul-sion a base de LP de soja. Une telle stimulation de lipolyse digestive avec les LP laitiers peut contribuer a expliquer l’augmentation plus importante de la concentration plasmatique de TG a 1 h puis sa diminution plus rapide. Conclusion Ces resultats suggerent que la qualite des lipides polaires utilises pour stabiliser une emulsion influence la lipolyse digestive et le metabolisme postprandial des lipides, dont les effets a long terme restent desormais a elucider.

Introduction Low-grade inflammation is now recognized as a hallmark of obesity pathophysiology. Recent interest has focused on the role of endotoxins absorbed during high fat meals. LBP and sCD14 have also been suggested as clinical markers of endotoxemia and 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 overfeeding-induced weight gain according to the changes of LBP/sCD14 ratio in plasma. Patients et methodes Eighteen lean to overweight subjects were submitted to overfeeding (OF) during 8 weeks (+ 760 kcal/day). Endotoxemia, sCD14, LBP and IL-6 were measured before and after OF at fasting (n = 18), and in the postprandial phase after an 882-kcal test meal in a subcohort (n = 8). Resultats In the cohort, no effect of OF was observed on fasting IL-6 but OF induced an increase of LBP/sCD14 ratio (P = 0,017). Subjects were divided into tertiles regarding their variation of LBP/sCD14 ratio due to OF. Subjects in the highest tertile (+ 90 % of LBP/sCD14 ratio) increased plasma IL-6 (+ 26%) compared with the lowest tertile (no increase of LBP/sCD14 ratio ; − 31 % of plasma IL-6 ; P Conclusion Overfeeding increases postprandial endotoxemia but the inflammatory outcome appears to be modulated by the handling of endotoxins by different transporters in plasma. This study supports a new concept whereby the setup of low-grade inflammation during the initial phase of weight gain is linked to the relative variations of LBP and sCD14.

Introduction L’obesite et le diabete sont des pathologies nutritionnelles devenues l’un des problemes majeurs de sante publique notamment par ses consequences cardiovasculaires. Les etudes physiopathologiques recentes ont montre le role de l’inflammation dans la genese de ce risque cardiovasculaire et mis en evidence les liens entre nutrition et inflammation. Les donnees recentes de la litterature nous amenent a emettre l’hypothese que lors d’une alimentation riche en lipides, des endotoxines de la flore intestinale seraient absorbees. Ces dernieres contribueraient a l’etablissement d’un etat inflammatoire. Nous avons donc souhaite elucider le role des lipides alimentaires ingeres sur l’absorption des endotoxines de la flore intestinale. Materiels et methodes Pour cela, nous avons suivi pendant 6 heures l’evolution de l’endotoxemie plasmatique chez des rats ayant ete gaves soit avec du serum physiologique, soit avec de l’huile de tournesol, soit avec une emulsion de cette meme huile. Resultats Nos resultats montrent que la digestion des lipides est plus importante pour l’emulsion que pour l’huile (delta max triglycerides = 2,2 ± 0,9 mM versus 1,1 ± 0,5 mM respectivement). De meme, nous avons ainsi mis en evidence que la solution d’emulsion conduisait a une accumulation d’endotoxines 2,3 fois plus importante que celle d’huile (AUC positive = 150,3 ± 90,9 versus 65,6 ± 62,2), et 7 fois plus que celle de serum (AUC positive = 20,4 ± 15,6). Par consequent, les valeurs de triglycerides et d’endotoxines sont tres fortement correles (r 2 = 0,97) chez le rat soumis a un gavage avec des solutions lipidiques differentes. Conclusion Ces resultats demontrent que l’ingestion de lipides alimentaires conduit a une accumulation des endotoxines plasmatiques et ce d’autant plus que ces lipides sont donnes sous la forme d’emulsion. En plus de la quantite de lipide, nos resultats montrent donc que leur structure pourrait jouer un role important sur l’absorption des endotoxines de la flore intestinale.

Rationnel L’inflammation a bas bruit est aujourd’hui reconnue comme une caracteristique metabolique majeure en situation d’obesite qui augmente les risques d’insulinoresistance et de maladies cardiovasculaires. Parmi les facteurs possibles declenchant et entretenant cette inflammation, la litterature recente et nos travaux ont revele le role de l’absorption des lipopolysaccharides (LPS, aussi appeles endotoxines) du microbiote intestinal durant la digestion des lipides alimentaires. Nous avons recemment montre chez l’animal que la resultante inflammatoire d’un regime hyperlipidique est aussi etroitement associee aux types de transporteurs et recepteurs plasmatiques des LPS : LBP, sCD14. Patients et methodes Dans nos recentes etudes chez l’homme, des volontaires sains de poids normal (20 Resultats En aigu, l’augmentation des apports en lipides est associee a une augmentation de l’endotoxemie circulante aussi bien chez les sujets de poids normal que chez les obeses. Le profil associe en LBP et sCD14 differe entre normoponderes et obeses. Suite a une augmentation chronique des apports en lipides, l’augmentation d’inflammation metabolique est associee aux modifications d’endotoxemie a jeun et en periode postprandiale. Conclusion Nos resultats montrent ainsi que l’augmentation des apports en lipides contribue a l’inflammation metabolique par des voies impliquant les endotoxines et leurs recepteurs.

Introduction L’obesite et le diabete sont des pathologies nutritionnelles devenues l’un des problemes majeurs de sante publique notamment par ses consequences cardiovasculaires. Les etudes physiopathologiques recentes ont montre le role de l’inflammation dans la genese de ce risque cardiovasculaire et mis en evidence les liens entre nutrition et inflammation. Les donnees recentes suggerent que lors d’une alimentation riche en lipides, des endotoxines de la flore intestinale seraient absorbees, pouvant ainsi contribuer a l’etablissement et au maintien d’un etat inflammatoire a bas bruit. Materiels et Methodes Nous avons donc souhaite elucider le role de la digestion des lipides alimentaires sur l’absorption des endotoxines de la flore intestinale chez le rat et l’homme. Nous avons suivi l’endotoxemie plasmatique chez des rats gaves soit avec du serum physiologique, soit avec de l’huile de tournesol, soit avec une emulsion de cette huile. Chez l’homme, nous avons suivi l’endotoxemie et l’inflammation pendant la digestion d’un repas contenant 33 g de lipides. Resultats Nos resultats chez le rat montrent que la lipemie postprandiale est plus elevee pour l’emulsion que pour l’huile (p Conclusion Ces resultats montrent qu’un repas contenant des lipides conduit a une augmentation de l’endotoxemie au cours de la digestion, phenomene pouvant etre augmente par l’emulsification. Ainsi, optimiser la structuration des lipides alimentaires pourrait etre une strategie pour limiter l’inflammation postprandiale en modulant l’absorption des endotoxines de la flore intestinale.