Deregulated lipid sensing by intestinal CD36 in diet-induced hyperinsulinemic obese mouse model

The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of intestinal lipid absorption in MetS mice, it accounted for only 17% after 4 h due to the secretion of larger size TRL. The MetS mice displayed accentuated postprandial hypertriglyceridemia up to 3 h due to a defective TRL clearance. These alterations reflected a delay in lipid induction of genes for key proteins of TRL formation (MTP, L-FABP) and blood clearance (ApoC2). These abnormalities associated with blunted lipid sensing by CD36, which is normally required to optimize jejunal formation of large TRL. In MetS mice CD36 was not downregulated by lipid in contrast to control mice. Treatment of controls with the proteosomal inhibitor MG132, which prevented CD36 downregulation, resulted in blunted lipid-induction of MTP, L-FABP and ApoC2 gene expression, as in MetS mice. Absence of CD36 sensing was due to the hyperinsulinemia in MetS mice. Acute insulin treatment of controls before lipid administration abolished CD36 downregulation, lipid-induction of TRL genes and reduced postprandial triglycerides (TG), while streptozotocin-treatment of MetS mice restored lipid-induced CD36 degradation and TG secretion. In vitro, insulin treatment abolished CD36-mediated up-regulation of MTP in Caco-2 cells. In conclusion, HFD treatment impairs TRL formation in early stage of lipid absorption via insulin-mediated inhibition of CD36 lipid sensing. This impairment results in production of smaller TRL that are cleared slowly from the circulation, which might contribute to the reported association of CD36 variants with MetS risk

Modification du mode de vie et longueur des télomères : revue systématique et méta- analyse

Background: we aimed to conduct a systematic review and meta-analysis to assess the effects of lifestyle intervention on telomere length (TL).Method: PubMed, Cochrane, Embase, and ScienceDirect were searched for studies reporting TL before and after a lifestyle intervention. We computed random-effects meta-analysis on TL at baseline between groups, within intervention group and control group after versus before intervention, and on changes in TL between groups. Sensitivity analyses were conducted after exclusion of studies outside funnel plots and keeping only RCT. Meta-regressions were computed to search for influential factors of TL.Results: we included 20 studies for a total of 2995 patients (mean: 50.3 years old, 77% women): 2045 individuals following an intervention and 950 controls. TL did not differ at baseline between intervention and control groups. Intervention was physical activity ± diet (n= 13 studies), diet (n= 1), stress management (n= 4), and supplementation (n= 2). The physical activity ± diet group had an increase in TL (Effect size 0.17, 95%CI 0.03 to 0.31, p= 0.020) using changes within the intervention group, whereas TL shortened in the control group (-0.32, -0.61 to -0.02, p= 0.037). TL was longer in the physical activity ± diet intervention group (0.24, 0.08 to 0.40, p= 0.004) compared to controls after the intervention. Sensitivity analysis after exclusion from meta-funnel gave similar results to only RCT. Meta-regressions demonstrated that combining strength and endurance exercise increased TL more than endurance alone (Coefficient 0.51, 95%CI 0.19 to 0.81, p= 0.004) or strength alone (0.74, 0.37 to 1.12, p= 0.001).Conclusion: a lifestyle intervention with physical activity ± diet can increase telomere length, independently of population characteristics or baseline TL. Combining strength and endurance may be the most beneficial exercise on TL.Contexte : nous avons réalisé une revue systématique et une méta-analyse pour évaluer les effets d'une modification du mode de vie sur la longueur des télomères (LT).Méthode : nous avons recherché dans PubMed, Cochrane, Embase et ScienceDirect, les études rapportant la LT avant et après une intervention sur le mode de vie. Plusieurs méta-analyses sur la LT ont été réalisées : initialement pour comparer les groupes, au sein du groupe intervention et du groupe contrôle avant et après l'intervention, et en comparant les deux groupes sur les changements de LT. Des méta régressions ont été calculées pour rechercher des facteurs influençant la LT.Résultats : nous avons inclus 20 études pour un total de 2995 patients : 2045 individus dans le groupe Intervention et 950 contrôles. La LT ne différait pas initialement entre les deux groupes. Les interventions étaient : activité physique ± alimentation (n = 13 études), alimentation (n = 1), gestion du stress (n = 4) et supplémentation (n = 2). Le groupe activité physique ± alimentation montrait une augmentation de la LT (taille d’effet 0.17, IC à 95 % 0.03 à 0.31, p = 0.020) au sein du groupe Intervention, tandis que les télomères raccourcissaient dans le groupe contrôle (-0.32, -0.61 à -0.02, p = 0.037). Concernant les changements au cours de l'intervention, la LT était plus longue dans le groupe activité physique ± alimentation (0.24, 0.08 à 0.40, p = 0.004) par rapport au groupe contrôle. Les méta-régressions ont démontré qu’associer force et endurance augmentait plus la LT que l'endurance seule (coefficient 0.51, IC à 95 % 0.19 à 0.81, p = 0.004) ou la force seule (0.74, 0.37 à 1.12, p = 0.001).Conclusion : une modification du mode de vie combinant activité physique et alimentation saine peut augmenter la LT, indépendamment des caractéristiques de la population ou de la LT au départ. Associer force et endurance parait plus bénéfique sur la LT

Impact of the metabolic syndrome on the oro-intestinal tract : prevention by a mix of micronutrients

La protéine CD36 est un senseur aux AGLC au niveau des papilles gustatives et des entérocytes, impliqué dans la détection gustative des lipides et dans l’optimisation de la synthèse des CM. Notre 1er objectif a été de déterminer si le syndrome métabolique (MS) était associé à une altération de la détection oro-intestinale des AGLC. A l’aide de modèles murins de MS (régimes riches en AGS), nous avons montré que le MS est associé à une moindre sensibilité gustative aux sucres et aux lipides et à une altération de la synthèse des CM à l’origine d’une hypertriglycéridémie postprandiale. Cette modification est associée à une absence de dégradation de CD36 classiquement médiée par les AGLC. Cette altération conduit à un retard d’induction de l’expression des gènes impliqués dans la synthèse de CM moins bien dégradés au niveau sanguin. Selon nos résultats l’hyperinsulinémie en MS pourrait être à l’origine de l’absence de dégradation de CD36. Au niveau oral il a aussi été montré que l’absence de dégradation de CD36 est associée à une altération de la signalisation calcique probablement à l’origine d’un seuil de détection plus élevé des AGLC. Le MS se caractérise donc par un problème de détection des lipides au niveau de la sphère oro-digestive qui favoriserait hyperphagie et hypertriglycéridémie postprandiale. Le 2e objectif a été de déterminer si le XXS (polyphénols) pouvait prévenir le MS. La supplémentation en XXS diminue la prévalence du MS, du fait d’une action anti-obésité associée à un maintien du seuil de détection des lipides et une augmentation de l’activité. Ainsi, la détection oro-intestinale des lipides semble être une cible pertinente pour lutter contre la mise en place du MSCD36 is a LCFA sensor in gustatory papillae and enterocytes. CD36 is implicated in the gustatory detection of lipids and in optimized CM synthesis. Our first goal was to determine if the metabolic syndrome (MS) was associated with alteration of the oro-intestinal detection of LCFA. Using a murine model of diet induced MS (saturated high fat diets) we shown that the MS is associated with a decrease in lipids and sugar gustatory sensitivity and an alteration in CM synthesis which contributes to the postprandial hypertriglyceridemia. This modification is associated with an absence of CD36 protein degradation classically triggered by LCFA. This alteration leads to a delay in the stimulation of the gene expression involved in the synthesis of CM less well cleared into the blood. Our data shows that the hyperinsulinemia on MS could cause the abolition of CD36 protein degradation. Other data obtained on gustatory papillae demonstrates that the absence of CD36 degradation is associated with an alteration of the LCFA induced calcium-signaling and that probably causes the increase in LCFA detection threshold. Thus, the MS is characterized by an alterated dietary lipids detection by the oro-intestinal tract which could promote overeating and postprandial hypertriglyceridemia. The second goal was to determine if the XXS (polyphenols) could prevent the appearance of the MS. The XXS supplementation decreases the syndrome prevalence, by exerting an anti-obesity activity associated with a LCFA detection threshold preservation and an increased activity. Thus, dietary lipids detection by gustatory papillae and intestine could represent a relevant target in order to prevent MS appearanc

93 Effect of replacing part of concentrates with pelleted alfalfa on squamous gastric ulcers in exercised trotters.

International audienceHorses at heavy work have a high prevalence of Equine Squamous Gastric Disease (ESGD). Exposure of the squamous mucosa to HCl causes damages, which can be more severe with acids produced by bacterial fermentation of starch and soluble sugars at pH ≤ 4. Among low-starch feedstuffs commonly fed to horses, alfalfa (Medicago sativa) has the strongest buffering capacity, and promising data on its healing impact have been observed in preliminary trials. In this field study, the effect of alfalfa was investigated on ESGD prevention and healing in trained horses. In 4 training centers, 80 exercised trotters (“very heavy work” based on NRC 2007) and housed in individual boxes were followed for 42 d. Gastroscopies were performed on D0, D21, D42 by an equine practitioner in a blind assessment. ESGD severity was scored using the EGUS Council 0–4 scoring system. On D0, horses were divided into 2 homogeneous groups on each center based on ESGD initial score, age and sex. Horses in control group (CON; n = 40) kept their previous ration (hay ad lib and 6.6 ± 1.8kg pellets; 4.5 ± 1.5g starch/kg BW/d). In the alfalfa group (ALF; n = 40), 50% (vol/vol) of pelleted concentrates were replaced by pelleted dehydrated alfalfa (hay ad lib and 6.3 ± 1.6kg pellets; 2.3 ± 0.7g starch/kg BW/d). Rations were almost isoenergy and isoprotein per center. Training continued without difference between groups. Horses were categorized in “no or mild ulcerations” (NMU – grades 0, 1, 2) and “severe ulcerations” (SU – grades 3, 4). Among the NMU horses at D0 (n = 49), preventive effect of the diet was determined by comparing number of NMU and SU horses at D21 and D42 using a Chi-2 test. Curative effect was evaluated by comparing number of NMU and SU horses at D21 and D42 among the SU horses at D0 (n = 31). No significant effect of the diet was measured on ESGD prevention or healing. In our study, ALF rations remained higher in starch compared with previous studies. In addition, in the 2 trials that showed a beneficial effect of alfalfa, horses were not intensively trained and alfalfa was fed as fodder. Feeding alfalfa pellets may have limited the preventive effect associated with saliva and formation of a protective layer on top of the gastric chyme

O04 Le sensing intestinal des lipides alimentaires médié par CD36 est-il altéré en cas de syndrome métabolique ?

International audience[Pas de résumé

Effect of diet composition on glandular gastric disease in horses

International audienceBackground: Nutritional factors are suggested to influence the incidence and severity of glandular gastric disease (GGD) in horses.Objectives: To retrospectively assess whether dietary fermentable carbohydrates increase the severity of GGD and to prospectively evaluate whether the partial substitution of concentrates by dehydrated alfalfa would decrease GGD severity scores.Animals: In total, 82 trotters from 4 training centers exercised ≥5 days/week.Methods: Multicenter retrospective observational study, and prospective 2-arm randomized trial. Glandular mucosae were observed by gastroscopy and scored (0-4 severity scale) at day 0 (D0). Biochemical composition of the diet fed was compared between ulcerated and nonulcerated groups. After D0, horses either received the same diet (control, n = 41) or pelleted dehydrated alfalfa substituting 50% concentrates (alfalfa, n = 41). Glandular scores were recorded in both groups after 21 (D21) and 42 days (D42). The first end point was a successful outcome, defined as a horse with a glandular score of 2 to 4 on D0, decreasing to a score of 0 to 1 on days 21 or 42.Results: Horses scored 0 to 1 at D0 ingested more (P = .01) soluble sugars from concentrates than those scored 2 to 4 before D0 (77.5 g/kg BW; 95% confidence interval [CI]: 71.1-84.0, vs 59.1 g/kg BW; 95% CI: 48.0-70.3), whereas starch intake did not differ between groups (P = .24). Among horses scored 2 to 4 at D0, fewer were scored 2 to 4 in the alfalfa group (1 out of 6) compared with the control group (6 out of 6) at D42 (P = .02). Clinical success was 47.7 times more likely in horses fed alfalfa compared with horses in the control group (95% CI: 1.6-1422.8).Conclusion and clinical importance: Relationships were found between diet composition and integrity of the glandular mucosa. Feeding pelleted dehydrated alfalfa could help to reduce the incidence and severity of GGD

11 Assessment of the impact of age on fecal microbial ecosystem in horses

International audienceIn humans, aging influences gut microbiota diversity and structure. In horses, modifications in gut microbiota could also occur, potentially leading to alteration in digestion and metabolism, development of diseases and even behavioral changes. Such modifications can affect microbial functions and consequently digestive capabilities. The aim of this in vivo study was to assess the age-related variations of microbial activity and physical parameters in the equine fecal ecosystem. The study population was composed of 50 horses (6–30 years old, geldings and mares from different breeds) conducted outdoors in the same sanctuary. Before the study, horses were dewormed and a dental examination was performed. They were gradually adapted during 1 week to the experimental diet (hay ad libitum + 860g muesli/horse/day). After 3 weeks of dietary management, naturally voided feces were collected individually for determination of pH, dry matter (DM), and fermentation end products concentrations (lactate and volatile fatty acids (VFA)). Age was correlated to each parameter (R software) and Pearson correlation coefficients were calculated. A GLM procedure was performed to compare the 5 age classes considered. Lactate and total VFA concentrations, propionate and iso-butyrate proportions were not correlated with age. Fecal pH and acetate (C2) proportion decreased with age, while DM, butyrate (C4), iso-valerate (iC5) and valerate (C5) proportions increased with age (Table 1). The fecal pH (P = 0.024), DM (P = 0.014), C4 (P < 0.001) and C5 (P < 0.001) proportions were different between elder horses (≥26 years) and younger (Table 1). These preliminary data suggest age-related modifications in digestion or metabolites absorption. Variation in microbiota activity and/or composition might explain some of these modifications. Bacterial structure and diversity in fecal ecosystem would provide complementary information to understand digestive evolution with age

Changes of faecal bacterial communities and microbial fibrolytic activity in horses aged from 6 to 30 years old

International audienceHorse owners and veterinarians report that from the age of 15, their horses can lose body condition and be more susceptible to diseases. Large intestinal microbiome changes may be involved. Indeed, microbiota is crucial for maintaining the condition and health of herbivores by converting fibres into nutrients. This study aimed to compare the faecal microbiome in horses aged from 6 to 30 years old (yo), living in the same environment and consuming the same diet, in order to assess whether the parameters changed linearly with age and whether there was a pivotal age category. Fifty horses were selected from the same environment and distributed across four age categories: 6–10 (n = 12), 11–15 (n = 11), 16–20 (n = 13), and 21–30 (n = 14) yo. All horses had no digestive problems, had teeth suitable for consuming their feed, and were up to date with their vaccination and deworming programmes. After three weeks of constant diet (ad libitum hay and 860 g of concentrate per day), one faecal sample per horse was collected on the same day. The bacterial communities’ richness and intra-sample diversity were negatively correlated with age. There was a new distribution of non-beneficial and beneficial taxa, particularly in the 21–30 yo category. Although the faecal concentration of short-chain fatty acids remained stable, the acetate proportion was negatively correlated with age while it was the opposite for the proportions of butyrate, valerate, and iso-valerate. Additionally, the faecal pH was negatively correlated with age. Differences were more pronounced when comparing the 6–10 yo and 21–30 yo categories. The values of the parameters studied became more dispersed from the 16–20 yo category onwards, which appeared as a transitional moment, as it did not differ significantly from the younger and older categories for most of these parameters. Our data suggest that the microbiome changes with age. By highlighting the pivotal age of 16–20, this gives the opportunity to intervene before individuals reach extremes that could lead to pathological conditions

From fatty-acid sensing to chylomicron synthesis: Role of intestinal lipid-binding proteins

International audienceToday, it is well established that the development of obesity and associated diseases results, in part, from excessive lipid intake associated with a qualitative imbalance. Among the organs involved in lipid homeostasis, the small intestine is the least studied even though it determines lipid bioavailability and largely contributes to the regulation of postprandial hyperlipemia (triacylglycerols (TG) and free fatty acids (FFA)). Several Lipid-Binding Proteins (LBP) are expressed in the small intestine. Their supposed intestinal functions were initially based on what was reported in other tissues, and took no account of the physiological specificity of the small intestine. Progressively, the identification of regulating factors of intestinal LBP and the description of the phenotype of their deletion have provided new insights into cellular and molecular mechanisms involved in fat absorption. This review will discuss the physiological contribution of each LBP in the main steps of intestinal absorption of long-chain fatty acids (LCFA): uptake, trafficking and reassembly into chylomicrons (CM). Moreover, current data indicate that the small intestine is able to adapt its lipid absorption capacity to the fat content of the diet, especially through the coordinated induction of LBP. This adaptation requires the existence of a mechanism of intestinal lipid sensing. Emerging data suggest that the membrane LBP CD36 may operate as a lipid receptor that triggers an intracellular signal leading to the modulation of the expression of LBP involved in CM formation. This event could be the starting point for the optimized synthesis of large CM, which are efficiently degraded in blood. Better understanding of this intestinal lipid sensing might provide new approaches to decrease the prevalence of postprandial hypertriglyceridemia, which is associated with cardiovascular diseases, insulin resistance and obesity

Mécanisme d’absorption intestinale des acides gras à longue chaîne : rôle émergent du CD36

International audienceExcessive lipid intake, associated with a qualitative imbalance, favors the development of obesity and associated diseases. Among the organs involved in lipid homeostasis, the small intestine remains the most poorly known although it is responsible for the lipid bioavailability and largely contributes to the regulation of postprandial hypertriglyceridemia. The mechanism of long chain fatty acid (LCFA) intestinal absorption is not totally elucidated. The synthesis of recent literature indicates that the intestine is able to adapt its absorption capacity to the fat content of the diet. This adaptation takes place through a fat-coordinated induction of LBP and apolipoproteins. CD36 could operate as a lipid sensor responsible for a transducing signal related to the lipid content of the diet at the origin of this intestinal adaptation. This lipid-mediated metabolic response may lead to the formation of large chylomicrons rapidly degraded in the blood. All together, these new data indicate that this intestinal lipid sensing mechanism may be a therapeutic target for reducing the postprandial hypertriglyceridemia and associated cardiovascular risks.L’apport excessif de lipides, associé à un déséquilibre qualitatif, favorise le développement de l’obésité et des maladies associées. Parmi les organes impliqués dans l’homéostasie lipidique, l’intestin est le moins étudié alors qu’il contribue à la biodisponibilité des lipides et à l’hypertriglycéridémie postprandiale. Le mécanisme d’absorption des lipides n’est pas totalement élucidé mais, contrairement à ce qui est établi, l’intestin adapte ses capacités d’absorption en fonction de la quantité de lipides du régime. Cette adaptation s’exerce via la modulation des gènes impliqués dans la formation des chylomicrons, comme les lipid-binding proteins (LBP) et certaines apolipoprotéines. Une LBP membranaire, le CD36 serait un senseur des lipides entérocytaires qui, via la transduction d’un signal intracellulaire, déclencherait l’induction du niveau des protéines optimisant la sécrétion de chylomicrons plus rapidement dégradés au niveau sanguin. Le CD36 constituerait une nouvelle cible permettant de réduire l’hypertriglycéridémie postprandiale, facteur de risque des maladies cardiovasculaires