Role of pattern recognition receptors and microbiota-derived ligands in obesity

Obesity is associated with activation of low-grade inflammation in tissues metabolically relevant for the regulation glucose homeostasis. The gut microbiota has been extensively linked to the inflammatory responses observed during obesity emphasizing the interconnection between host immunity and metabolism during obesity. Gut microbiota together with alteration of the gut barrier functions provide a myriad of circulating ligands for the pattern recognition receptors (PRRs) expressed in innate immune cells and nonimmune cells. PRR-dependent signalling drives the expression of a wide range of genes beyond the inflammatory response depending on the specific functions of the targeted cells and on the physiological context. PRRs activation can have opposite effects on host metabolic inflammation. Nucleotide-binding oligomerization domain 1 (NOD1) or NOD-like Receptor pyrin domain containing 3 (NLRP3) activation promote metabolic inflammation and insulin resistance while NOD2 activation improves insulin sensitivity and glucose homeostasis during obesity. Toll-like receptors (TLRs) 2, 4 and 5 also display specific effects on metabolic tissues. TLR5 deficient mice are prone to obesity and inflammation in response to high fat diet, while injection of TLR5 ligand, flagellin, has a protective effect toward diet-induced obesity. To the opposite TLR2 and 4 activations are associated with deleterious metabolic outcome during obesity. TLR4 activation enhances metabolic inflammation and insulin resistance and TLR2 via its activation by molecules derived from the gut microbiota favours the onset of obesity. It is now clear that activation of PRRs by bacterial derived molecules plays a key role in the host metabolic regulation. PRRs are expressed in various cell types complicating the understanding of the mechanisms underlying the relationship between PRRs activation/silencing and metabolic inflammation in obesity context. This review presents an overview of the current understanding of the interrelationship between the gut microbiota and PRRs, with a focus on its consequences for obesity and related metabolic diseases

273 New cardiac biomarkers after marathon in woman

In a prospective study we evaluated kinetic of hFABP, CAIII and GPBB during the 2008 Marathon du Médoc by 67 healthy volunteered. Blood were collected at baseline (T1), immediately after (T2) and 3 h after (T3). Biomarkers were assayed by Cardiac array on Evidence Investigator (EI) RANDOX, cTnI and myoglobine by Dimension RxL too. 10 (5%) TnIc values disagreed between RxL and EI, all at T2 and T3. cTnI (EI) was negative in all subjects before, increased transiently in 4 (6%) at T2 then normalized. Increased ratio of Myo to FABP from [4-46] to [5-1208] then [5-43] indicated that Myo was more likely to originate from muscle. hFABP normal at T1 but for one, increased for all but one at T2 [4->150] and T3 [5->150]. CAIII increased from [8-68 ng/mL] to [45->145] then [57->145] indicated skeletal muscle damage. GPBB baseline was in [2-7 ng/mL] but for one. 13 (19%) rates increased at T2 [8-27], which 7 returned to baseline after 3 h and 6 remained high. 6 (9%) increased only at T3 [8,5-141]. Combination of markers showed that by the 4 women who had elevated cTnI (T3), Myo, hFABP and CAIII increased in all cases and GPBB in two. GPBB, presented as released early from injured myocardial cells, increased however in 19 (28%) women after marathon. Moderate elevation of GPBB would more likely reflect active glycogenolysis and heart fatigue than injury. These new markers don’t offer adequate cardiospecificity to rule out myocardial damage in runners

The fate of the duplicated androgen receptor in fishes: a late neofunctionalization event?

<p>Abstract</p> <p>Background</p> <p>Based on the observation of an increased number of paralogous genes in teleost fishes compared with other vertebrates and on the conserved synteny between duplicated copies, it has been shown that a whole genome duplication (WGD) occurred during the evolution of Actinopterygian fish. Comparative phylogenetic dating of this duplication event suggests that it occurred early on, specifically in teleosts. It has been proposed that this event might have facilitated the evolutionary radiation and the phenotypic diversification of the teleost fish, notably by allowing the sub- or neo-functionalization of many duplicated genes.</p> <p>Results</p> <p>In this paper, we studied in a wide range of Actinopterygians the duplication and fate of the androgen receptor (AR, NR3C4), a nuclear receptor known to play a key role in sex-determination in vertebrates. The pattern of AR gene duplication is consistent with an early WGD event: it has been duplicated into two genes AR-A and AR-B after the split of the Acipenseriformes from the lineage leading to teleost fish but before the divergence of Osteoglossiformes. Genomic and syntenic analyses in addition to lack of PCR amplification show that one of the duplicated copies, AR-B, was lost in several basal Clupeocephala such as Cypriniformes (including the model species zebrafish), Siluriformes, Characiformes and Salmoniformes. Interestingly, we also found that, in basal teleost fish (Osteoglossiformes and Anguilliformes), the two copies remain very similar, whereas, specifically in Percomorphs, one of the copies, AR-B, has accumulated substitutions in both the ligand binding domain (LBD) and the DNA binding domain (DBD).</p> <p>Conclusion</p> <p>The comparison of the mutations present in these divergent AR-B with those known in human to be implicated in complete, partial or mild androgen insensitivity syndrome suggests that the existence of two distinct AR duplicates may be correlated to specific functional differences that may be connected to the well-known plasticity of sex determination in fish. This suggests that three specific events have shaped the present diversity of ARs in Actinopterygians: (i) early WGD, (ii) parallel loss of one duplicate in several lineages and (iii) putative neofunctionalization of the same duplicate in percomorphs, which occurred a long time after the WGD.</p

Lack of Hypothalamus Polysialylation Inducibility Correlates With Maladaptive Eating Behaviors and Predisposition to Obesity

High variability exists in individual susceptibility to develop overweight in an obesogenic environment and the biological underpinnings of this heterogeneity are poorly understood. In this brief report, we show in mice that the vulnerability to diet-induced obesity is associated with low level of polysialic acid-neural cell adhesion molecule (PSA-NCAM), a factor of neural plasticity, in the hypothalamus. As we previously shown that reduction of hypothalamic PSA-NCAM is sufficient to alter energy homeostasis and promote fat storage under hypercaloric pressure, inter-individual variability in hypothalamic PSA-NCAM might account for the vulnerability to diet-induced obesity. These data support the concept that reduced plasticity in brain circuits that control appetite, metabolism and body weight confers risk for eating disorders and obesity

Métabolisme des lipides dans la semence de dindon : (conséquences sur la conservation des spermatozoïdes)

Chez le dindon, l'insémination artificielle impose une étape de conservation in vitro de la semence qui entraîne une baisse de la fertilité. Les phospholipides participent à l'adaptation des cellules au cours du stockage in vitro. L'objectif de ce travail est de vérifier si la baisse de fertilité résulte de l'altération des lipides des gamètes. La conservation liquide entraîne une dégradation des phospholipides des spermatozoïdes. Les quantités de cholestérol, d'acides gras et de phospholipides du plasma séminal demeurent inchangées. Trois hypothèses susceptibles d'expliquer cette perte en phospholipide ont été étudiées : La péroxydation lipidique qui augmente dans la semence conservée chez les animaux âgés. Le métabolisme des acides gras endogènes, très peu actif, même en l'absence de substrat énergétique exogènes. La lyse enzymatique des phospholipides, rendue possible par la présence d'activités (lyso)phospholipases mise en évidence, au cours de cette étude, dans les spermatozoïdes et le plasma séminal. Il apparaît nécessaire de limiter la dégradation des phospholipides en inactivant les phospholipases avant la conservation in vitro.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Fructose and irritable bowel syndrome

International audienceIrritable bowel syndrome (IBS) is a chronic disorder characterised by recurrent abdominal pain or discomfort and transit disturbances with heterogeneous pathophysiological mechanisms. The link between food and gastrointestinal (GI) symptoms is often reported by patients with IBS and the role of fructose has recently been highlighted. Fructose malabsorption can easily be assessed by hydrogen and/or methane breath test in response to 25 g fructose; and its prevalence is about 22 % in patients with IBS. The mechanism of fructose-related symptoms is incompletely understood. Osmotic load, fermentation and visceral hypersensitivity are likely to participate in GI symptoms in the IBS population and may be triggered or worsened by fructose. A low-fructose diet could be integrated in the overall treatment strategy, but its role and implication in the improvement of IBS symptoms should be evaluated. In the present review, we discuss fructose malabsorption in adult patients with IBS and the interest of a low-fructose diet in order to underline the important role of fructose in IBS

Effect of dietary fructose on portal and systemic serum fructose levels in rats and in KHK-/- and GLUT5-/- mice

Elevated blood fructose concentrations constitute the basis for organ dysfunction in fructose-induced metabolic syndrome. We hypothesized that diet-induced changes in blood fructose concentrations are regulated by ketohexokinase (KHK) and the fructose transporter GLUT5. Portal and systemic fructose concentrations determined by HPLC in wild-type mice fed for 7 days 0% free fructose were 1 mM) with reversed portal to systemic gradients. Systemic fructose in wild-type and KHK(-/-) mice changed by 0.34 and 1.8 mM, respectively, for every millimolar increase in portal fructose concentration. Systemic glucose varied strongly with systemic, but not portal, fructose levels in wild-type, and was independent of systemic and portal fructose in KHK(-/-), mice. With ad libitum feeding for 12 wk, fructose-induced hyperglycemia in wild-type, but not hyperfructosemia in KHK(-/-) mice, increased HbA1c concentrations. Increasing dietary fructose to 40% intensified the hyperfructosemia of KHK(-/-) and the fructose-induced hyperglycemia of wild-type mice. Fructose perfusion or feeding in rats also caused duration- and dose-dependent hyperfructosemia and hyperglycemia. Significant levels of blood fructose are maintained independent of dietary fructose, KHK, and GLUT5, probably by endogenous synthesis of fructose. KHK prevents hyperfructosemia and fructose-induced hyperglycemia that would markedly increase HbA1c levels. These findings explain the hyperfructosemia of human hereditary fructosuria as well as the hyperglycemia of fructose-induced metabolic syndrome

Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK.

Marked increases in fructose consumption have been tightly linked to metabolic diseases. One-third of ingested fructose is metabolized in the small intestine, but the underlying mechanisms regulating expression of fructose-metabolizing enzymes are not known. We used genetic mouse models to test the hypothesis that fructose absorption via glucose transporter protein, member 5 (GLUT5), metabolism via ketohexokinase (KHK), as well as GLUT5 trafficking to the apical membrane via the Ras-related protein in brain 11a (Rab11a)-dependent endosomes are required for the regulation of intestinal fructolytic and gluconeogenic enzymes. Fructose feeding increased the intestinal mRNA and protein expression of these enzymes in the small intestine of adult wild-type (WT) mice compared with those gavage fed with lysine or glucose. Fructose did not increase expression of these enzymes in the GLUT5 knockout (KO) mice. Blocking intracellular fructose metabolism by KHK ablation also prevented fructose-induced upregulation. Glycolytic hexokinase I expression was similar between WT and GLUT5- or KHK-KO mice and did not vary with feeding solution. Gavage feeding with the fructose-specific metabolite glyceraldehyde did not increase enzyme expression, suggesting that signaling occurs before the hydrolysis of fructose to three-carbon compounds. Impeding GLUT5 trafficking to the apical membrane using intestinal epithelial cell-specific Rab11a-KO mice impaired fructose-induced upregulation. KHK expression was uniformly distributed along the villus but was localized mainly in the basal region of the cytosol of enterocytes. The feedforward upregulation of fructolytic and gluconeogenic enzymes specifically requires GLUT5 and KHK and may proactively enhance the intestine's ability to process anticipated increases in dietary fructose concentrations

Influence du microbiote et du régime (transition hyperlipidique) sur la plasticité neurogliale dans le bulbe olfactif chez le rat

International audienceIntroduction : Les rongeurs axéniques, dépourvus de microbiote, sont résistants aux régimes obésogènes (Rabot et al 2010), ce qui souligne l’importance du microbiote dans la régulation de la prise alimentaire. Ces effets pourraient passer par la production de métabolites qui participent aux signaux satiétogènes envoyés par le tube digestif au cerveau (van de Wouw et al 2017). Parmi les mécanismes potentiellement mis en jeu, nous avons évalué l’impact du microbiote sur le système olfactif, impliqué dans la prise alimentaire et la sensation de faim/satiété en modulant la perception et la valence des odeurs alimentaires. Méthodes : Nous avons comparé les régulations neuronales et gliales au niveau des glomérules du bulbe olfactif (BO), premier site d’intégration du signal olfactif, chez des rats conventionnels (C) ou axéniques (GF, Germ Free) soumis pendant deux jours à un régime hyperlipidique (HF, High Fat diet) ou maintenus en régime standard (C, Chow diet). Résultats : La transition au régime HF induit une augmentation de la consommation énergétique pendant les premières 24 heures suivie d’un retour à une consommation normale dans les deux jours sous l’effet de l’adaptation de la prise alimentaire aux apports énergétiques. Cette adaptation au régime HF est plus faible chez les rats axéniques que chez les rats conventionnels. Nous avons évalué l’impact au niveau du système olfactif en analysant plusieurs marqueurs de plasticité dans la couche glomérulaire des bulbes olfactifs par immunohistochimie : la plasticité morphologique astrocytaire (GFAP) comme marqueur de faim/satiété (Daumas-Meyer et al 2018), l’activité dopaminergique (TH) et sérotoninergique (5-HT) comme marqueurs des changements de perception olfactive, le nombre et la morphologie des cellules microgliales (Iba1) impliquées dans les défenses et le renouvellement des neurones dans le BO. Nous n’avons pas observé de changements significatifs de ces marqueurs en réponse au microbiote (rats GF vs C) ou au régime HF. Nous observons cependant une faible diminution de l’activité dopaminergique en réponse au régime HF chez les rats conventionnels, et moins de ramifications microgliales en réponse au régime HF chez les rats axéniques. Conclusion : Ces résultats ne mettent pas en évidence de variations majeures des régulations glomérulaires entre les animaux conventionnels ou axéniques, mais des modulations subtiles du système olfactif pourraient contribuer à l’impact du microbiote sur le comportement alimentaire

Influence of the microbiota and a high fat diet transition on glomerular regulations in the olfactory bulb in rats

International audienc