Impact de la nature du régime, du statut pondéral et de la chirurgie bariatrique sur les dimensions neurocognitives, motivationnelles et limbiques du comportement alimentaire chez le mini porc Yucatan

National audienceLes habitudes alimentaires peuvent impacter les processus cognitifs et émotionnels. Dans le contexte del'obésité et des troubles alimentaires, comprendre les mécanismes liés à l'axe intestin- cerveau est crucialpour optimiser la prise en charge des patients.Dans cette expérience, des miniporcs Yucatan ont été exposés durant plusieurs semaines à un apportisocalorique d'aliment gras et sucré (Western diet, WD), puis à une alimentation hyper- calorique WDpour induire une obésité. Enfin, ils ont subi une restriction calorique (aliment standard STD) avecby-pass gastrique (BP) ou une chirurgie fantôme (Sham). A chacune de ces trois phases, les processuscognitifs, motivationnels, et émotionnels (test du ho/eboard à récompenses palatables), ainsi que leschoix alimentaires, ont été étudiés et interprétés en parallèle de données d'imagerie cérébrale (TEP).En phase 1, le régime WD n'altère globalement pas les performances de mémoire des animaux, ni leurstatut émotionnel ou motivationnel. L'aliment WD est systématiquement préféré en test de choix (P<0.01). Au stade obèse vs. normopondéral, les animaux mettent plus de temps à ter- miner le test duholeboard (P< 0.01), ont une motivation réduite pour les récompenses (latence P< 0.05, nombre devisites P< 0.001), un niveau d' attention inférieur (P< 0.05), semblent plus stressés (immobilité P< 0.01,vocalisations P< 0.001, exploration paroi P< 0.01), et amplifient les fiai rages (durée et occurrences, P<0.01). Les interventions Sham ou BP n'ont pas d'effet sur la mémoire, mais semblent rapprocher lesanimaux de leur phénotype comportemental à l'état normopondéral (durée test holeboard P< 0.05,motivation P< 0.05, vocalisation et exploration paroi P< 0.05). Lors du test de choix alimentaire, lesSham ingèrent davantage de nourriture (P< 0.05), mais le comportement de fiai rage n'est pas modifié.Le striatum dorsal fait partie des structures dont le métabolisme est altéré autant par le régime quepar l'obésité, tandis que l' hippocampe et le cortex cingulaire sont affectés par le traitement post-obésité(régime avec ou sans bypass)

Exposure to a sensory functional ingredient in the pig model modulates the blood-oxygen-level dependent brain responses to food odor and acute stress during pharmacological MRI in the frontostriatal and limbic circuits

International audienceIntroductionIn the present study, we examined the effects of a supplementation with a sensory functional ingredient (FI, D16729, Phodé, France) containing vanillin, furaneol, diacetyl and a mixture of aromatic fatty acids on the behavioural and brain responses of juvenile pigs to acute stress. MethodsTwenty-four pigs were fed from weaning with a standard granulated feed supplemented with the functional ingredient D16729 (FS animals, N = 12) or a control formulation (CT animals, N = 12). After a feed transition (10 days after weaning), the effects of FI were investigated on eating behaviour during two-choice feed preference tests. Emotional reactivity to acute stress was then investigated during openfield (OF), novel suddenly moving object (NSO), and contention tests. Brain responses to the FI and the two different feeds’ odour, as well as to an acute pharmacological stressor (injection of Synacthen®) were finally investigated with functional magnetic resonance imaging (fMRI). ResultsFS animals tended to spend more time above the functional feed ( p = 0.06) and spent significantly more time at the periphery of the arena during NSO ( p &lt; 0.05). Their latency to contact the novel object was longer and they spent less time exploring the object compared to CT animals ( p &lt; 0.05 for both). Frontostriatal and limbic responses to the FI were influenced by previous exposure to FI, with higher activation in FS animals exposed to the FI feed odor compared to CT animals exposed to a similarly familiar feed odor without FI. The pharmacological acute stress provoked significant brain activations in the prefrontal and thalamic areas, which were alleviated in FS animals that also showed more activity in the nucleus accumbens. Finally, the acute exposure to FI in naive animals modulated their brain responses to acute pharmacological stress. DiscussionOverall, these results showed how previous habituation to the FI can modulate the brain areas involved in food pleasure and motivation while alleviating the brain responses to acute stress

The ghrelin system follows a precise post-natal development in mini-pigs that is not impacted by dietary medium chain fatty-acids

International audienceThe ghrelin-ghrelin receptor (GHSR1) system is one of the most important mechanisms regulating food intake and energy balance. To be fully active, ghrelin is acylated with medium-chain fatty acids (MCFA) through the ghrelin-O-acetyl transferase (GOAT). Several studies reported an impact of dietary MCFA on ghrelin acylation in adults. Our study aimed at describing early post-natal development of the ghrelin system in mini-pigs as a model of human neonates and evaluating the impact of dietary MCFA. Suckled mini-pigs were sacrificed at post-natal day (PND) 0, 2, 5, and 10 or at adult stage. In parallel, other mini-pigs were fed from birth to PND10 a standard or a dairy lipid-enriched formula with increased MCFA concentration (DL-IF). Plasma ghrelin transiently peaked at PND2, with no variation of the acylated fraction except in adults where it was greater than during the neonatal period. Levels of mRNA coding pre-proghrelin (GHRL) and GOAT in the antrum did not vary during the post-natal period but dropped in adults. Levels of antral pcsk1/3 (cleaving GHRL into ghrelin) mRNA decreased significantly with age and was negatively correlated with plasma acylated, but not total, ghrelin. Hypothalamic ghsr1 mRNA did not vary in neonates but increased in adults. The DL-IF formula enriched antral tissue with MCFA but did not impact the ghrelin system. In conclusion, the ghrelin maturation enzyme PCSK1/3 gene expression exhibited post-natal modifications parallel to transient variations in circulating plasma ghrelin level in suckling piglets but dietary MCFA did not impact this post-natal development

Obesogenic diet leads to luminal overproduction of the complex IV inhibitor H 2 S and mitochondrial dysfunction in mouse colonocytes

International audienceObesity is characterized by systemic low-grade inflammation associated with disturbances of intestinal homeostasis and microbiota dysbiosis. Mitochondrial metabolism sustains epithelial homeostasis by providing energy to colonic epithelial cells (CEC) but can be altered by dietary modulations of the luminal environment. Our study aimed at evaluating whether the consumption of an obesogenic diet alters the mitochondrial function of CEC in mice. Mice were fed for 22 weeks with a 58% kcal fat diet (diet-induced obesity [DIO] group) or a 10% kcal fat diet (control diet, CTRL). Colonic crypts were isolated to assess mitochondrial function while colonic content was collected to characterize microbiota and metabolites. DIO mice developed obesity, intestinal hyperpermeability, and increased endotoxemia. Analysis of isolated colonic crypt bioenergetics revealed a mitochondrial dysfunction marked by decreased basal and maximal respirations and lower respiration linked to ATP production in DIO mice. Yet, CEC gene expression of mitochondrial respiration chain complexes and mitochondrial dynamics were not altered in DIO mice. In parallel, DIO mice displayed increased colonic bile acid concentrations, associated with higher abundance of Desulfovibrionaceae. Sulfide concentration was markedly increased in the colon content of DIO mice. Hence, chronic treatment of CTRL mouse colon organoids with sodium sulfide provoked mitochondrial dysfunction similar to that observed in vivo in DIO mice while acute exposure of isolated mitochondria from CEC of CTRL mice to sodium sulfide diminished complex IV activity. Our study provides new insights into colon mitochondrial dysfunction in obesity by revealing that increased sulfide production by DIO-induced dysbiosis impairs complex IV activity in mouse CEC

Protein Ingredient Quality within Infant Formulas Impacts Plasma Amino Acid Concentrations in Neonatal Minipiglets

International audienceBackground: Infant formulas (IFs), the only adequate substitute to human milk, are complex matrices that require numerous ingredients and processing steps that may impact protein digestion and subsequent amino acid (AA) absorption. Objectives: The objective was to understand the impact of the protein ingredient quality within IFs on postprandial plasma AA profiles. Methods: Four isonitrogenous and isocaloric IFs were produced at a semi-industrial scale using whey proteins from different origins (cheese compared with ideal whey) and denaturation levels (IF-A, -B, -C), and caseins with different supramolecular organizations (IF-C, -D). Ten Yucatan minipiglets (12- to 27-d-old) were used as a human infant model and received each IF for 3 d according to a Williams Latin square followed by a 2-d wash-out period. Jugular plasma was regularly sampled from 10 min preprandial to 4 h postprandial on the third day to measure free AAs, urea, insulin, and glucose concentrations. Data were statistically analyzed using a mixed linear model with diet (IFs), time, and sex as fixed factors and piglet as random factor.Results: IFs made with cheese whey (IF-A and -B) elicited significantly higher plasma total and essential AA concentrations than IFs made with ideal whey (IF-C and -D), regardless of the pre- and postprandial times. Most of the differences observed postprandially were explained by AA homeostasis modifications. IFs based on cheese whey induced an increased plasma concentration of Thr due to both a higher Thrcontent in these IFs and a Thr-limiting degrading capability in piglets. The use of a nonmicellar casein ingredient led to reduced plasma content of AA catabolism markers (IF-D compared with IF-C).Conclusions: Overall, our results highlight the importance of the protein ingredient quality (composition and structure) within IFs on neonatal plasma AA profiles, which may further impact infant protein metabolism

La réduction de la biogénèse mitochondriale des cellules épithéliales intestinales induite par la consommation de lipides alimentaires en excès est associée à une augmentation de la prolifération épithéliale et de la perméabilité intestinales chez la souris

International audienceIntroductionL'obésité et le surpoids sont associés à une inflammation de bas grade liée à des altérations de la barrière intestinale. La fonction mitochondriale des cellules épithéliales intestinales (CEI) joue un rôle majeur dans le maintien de l’homéostasie intestinale et pourrait être altérée par des changements du métabolisme lipidique des CEI, décrits dans l’obésité. L'objectif de cette étude était d'évaluer si la consommation d’un régime obésogène modifie la fonction mitochondriale des CEI et l’homéostasie intestinale chez la souris.Matériel et méthodesDes souris ont été nourries avec un régime contrôle (CTRL) ou un régime obésogène (DIO) pendant 22 semaines puis les CEI de jéjunum ont été isolées.RésultatsLes souris DIO ont développé une obésité caractérisée par une augmentation de l'endotoxémie par rapport aux souris CTRL et une stéatose entérocytaire. L'analyse de la fonction mitochondriale des CEI des souris DIO a révélé une diminution par deux de la respiration basale, associée à une moindre expression des complexes de la chaîne de respiration mitochondriale. De plus, le nombre de mitochondrie par CEI de souris DIO est diminué par deux par rapport aux CTRL, en lien avec une diminution de l’expression de gènes régulant la dynamique mitochondriale. En outre, la consommation d’un régime obésogène augmente la perméabilité jéjunale, l’expression de la claudine permissive Cldn2 ainsi que la prolifération des CEI.DiscussionCes résultats indiquent que la biogénèse mitochondriale des CEI est diminuée par la consommation d’un régime obésogène et participerait à la perte de l'homéostasie épithéliale, marquée par une prolifération accrue des CEI, une augmentation du nombre de cellules immatures et de l’expression de Cldn2, contribuant à l’augmentation de perméabilité intestinale

Development of a functional dairy snack containing oleoylethanolamide that reduces food intake in normal-weight and obese minipigs

Oleoylethanolamide (OEA) is a safe bioactive lipid that demonstrated strong anorexigenic properties in preclinical and clinical models. In order to evaluate the importance of OEA delivery kinetic on its anorectic properties, we developed OEA-containing dairy snacks with either a liquid or a semi-solid form. The OEA+ liquid snack, but not the semi-solid one, reduced by 14 and 18 % the amount of feed eaten by normal-weight and obese minipigs, respectively, in an eating behavior test performed 4 h after snack ingestion. In vitro digestion experiments revealed that OEA release in intestinal digesta was greatly enhanced when the snack was liquid compared to the semi-solid structure. Kinetic investigations of several plasma parameters after liquid snack ingestion points towards different potential mechanism depending upon the minipig weight status, with an effect of the OEA+ liquid snack likely on endocannabinoid and other related N-acylethanolamine metabolism in normal-weight minipigs and on ketogenesis in obese ones

Impact d'une exposition périnatale au sucre et au gras via le régime maternel sur le comportement, les adaptations, métaboliques et cérébrales de miniporcs Yucatan

National audienceIntroduction: A lot of evidences defend the existence of a relationship between a Western diet and the increase of obesity prevalence (OMS, 2011). Particularly, the quality of early nutrition has a long-term impact on the offspring’s phenotype and health status (Barker, 1989). The aim of our study was to explore in the Yucatan minipig model the impact of the maternal diet (High Fat Fructose diet, HFF versus standard diet, STD) during pregnancy and lactation on the cognitive and hedonic functions of the offspring at the adult age, through behavioural assessments and brain imaging, combined with metabolic and physiological explorations. A challenge with an obesogenic diet was then performed to assess its effects on eating behaviour, weight gain and blood parameters.Material & methods: Learning and memory performances were tested using the holeboard discrimination task, with a palatable food reward (M&M’s®), and an Alley maze test, independent from food reward. Eating behaviour was explored with a two-choice feed test and an operant conditioning test with progressive ratio. In parallel, the brain basal glucose metabolism was investigated using Positron Emission Tomography (PET) and the dopaminergic brain reward system (in particular the striatum) was explored using DAT-scan imaging. Biologic samples were collected for blood profiles and analysis of the gut microbiota activity (FFA).Results: We showed that early nutrition could indirectly impact cognitive performances, modulating the emotional status in a high-anxiogenic/low-motivating (maze) situation, but not in low-anxiogenic/high-motivating situation (holeboard). As a matter of fact, STD better succeeded in the maze, whereas no difference appeared during the holeboard test. During the feeding tests, HFF showed a tendency to eat more than STD group. Brain sub-activations in the anterior prefrontal cortex and accumbens nucleus, as well as impairment of the striatal dopaminergic system were observed, which may explain eating behavior differences between HFF and STD. On the other hand, HFF presented better lipids profiles than STD. After an obesogenic challenge, we surprisingly observed that STD ate and gained more weight than HFF, while HFF inflammatory status was higher than STD. Conclusion: All these results suggest that HFF maternal western diet had a deleterious impact on the neurocognitive functions, in a high stressful situation, of the offspring and modulated its responses to an obesogenic dietary challenge.Key words: nutritional imprinting, behavior, brain, reward system, memory, learning, minipig