Acylated Ghrelin and The Regulation of Lipid Metabolism in The Intestine.

Acylated ghrelin (AG) is a gastrointestinal (GI) peptide mainly secreted by the stomach that promotes cytosolic lipid droplets (CLD) hypertrophy in adipose tissues and liver. However, the role of AG in the regulation of lipid metabolism in the intestine remains unexplored. This study aimed at determining whether AG influences CLD production and chylomicron (CM) secretion in the intestine. The effects of AG and oleic acid on CLD accumulation and CM secretion were first investigated in cultured Caco-2/15 enterocytes. Intestinal lipid metabolism was also studied in Syrian Golden Hamsters submitted to conventional (CD) or Western (WD) diets for 8 weeks and continuously administered with AG or physiological saline for the ultimate 2 weeks. In cultured Caco-2/15 enterocytes, CLD accumulation influenced CM secretion while AG reduced fatty acid uptake. In WD hamsters, continuous AG treatment amplified chylomicron output while reducing postprandial CLD accumulation in the intestine. The present study supports the intimate relationship between CLD accumulation and CM secretion in the intestine and it underlines the importance of further characterizing the mechanisms through which AG exerts its effects on lipid metabolism in the intestine.

Two weeks of high-fat feeding disturb lipid and cholesterol molecular markers.

Metabolic disorders are often associated with liver steatosis and increased plasma cholesterol levels. However, the link between excessive lipid accumulation and impairments in cholesterol metabolism remains uninvestigated in the liver. Short term of high-fat diet (HFD) was previously shown to promote excessive lipid accumulation prior to the development of metabolic disorders. The present study intended to characterize how increases in liver fat alter the expression of several key regulators of hepatic cholesterol metabolism in response to a short-term HFD. Wistar rats were randomly submitted either to HFD (n = 8) or a regular chow diet (n = 8) for 14 days. Increases in triglycerides were highly significant (P < 0.01) in the liver but marginal in the plasma of HFD rats. In contrast, the HFD resulted in higher (P < 0.01) cholesterol levels in plasma but not in liver samples. Gene expression of key markers involved in cholesterol uptake (LDL particles) including low-density lipoprotein receptor-related protein-1 (LRP-1) and protein convertase subtilisin/kexin type 9 (PCSK9) along with ATP-binding cassette, superfamily G, member 5 (ABCG5) involved in cholesterol exportation via bile ducts was found to be higher (P < 0.05) in response to the HFD. In contrast, expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), involved in cholesterol synthesis, was downregulated in the liver. The data support the concept that excessive accumulation of lipids promptly alters the expression of key genes regulating cholesterol metabolism in the liver. On a clinical point of view, this indicates that increases in plasma cholesterol occur after a short-term HFD.

Gastrointestinal factors regulating lipid droplet formation in the intestine.

Cytoplasmic lipid droplets (CLD) are considered as neutral lipid reservoirs, which protect cells from lipotoxicity. It became clear that these fascinating dynamic organelles play a role not only in energy storage and metabolism, but also in cellular lipid and protein handling, inter-organelle communication, and signaling among diverse functions. Their dysregulation is associated with multiple disorders, including obesity, liver steatosis and cardiovascular diseases. The central aim of this review is to highlight the link between intra-enterocyte CLD dynamics and the formation of chylomicrons, the main intestinal dietary lipid vehicle, after overviewing the morphology, molecular composition, biogenesis and functions of CLD.

Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons.

Cannabinoids receptors have been reported to modulate synaptic transmission in many structures of the CNS, but yet little is known about their role in the prefrontal cortex where type I cannabinoid receptor (CB-1) are expressed. In this study, we tested first the acute effects of selective agonists and antagonist of CB-1 on glutamatergic excitatory postsynaptic currents (EPSCs) in slices of rat prefrontal cortex (PFC). EPSCs were evoked in patch-clamped layer V pyramidal cells by stimulation of layer V afferents. Monosynaptic EPSCs were strongly depressed by bath application (1 microM) of the cannabinoid receptors agonists WIN55212-2 (-50.4 +/- 8.8%) and CP55940 (-42.4 +/- 10.9%). The CB-1 antagonist SR141716A reversed these effects. Unexpectedly, SR141716A alone produced a significant increase of glutamatergic synaptic transmission (+46.9 +/- 11.2%), which could be partly reversed by WIN55212-2. In the presence of strontium in the bath, the frequency but not the amplitude of asynchronous synaptic events evoked in layer V pyramidal cells by stimulating layer V afferents, was markedly decreased (-54.2 +/- 8%), indicating a presynaptic site of action of cannabinoids at these synapses. Tetanic stimulation (100 pulses at 100 Hz, 4 trains) induced in control condition, no changes (n = 7/18), long-term depression (LTD; n = 6/18), or long-term potentiation (LTP; n = 5/18) of monosynaptic EPSCs evoked by stimulation of layer V afferents. When tetanus was applied in the presence of WIN 55,212-2 or SR141716-A (1 microM) in the bath, the proportion of "nonplastic" cells were not significantly changed (n = 7/15 in both cases). For the plastic ones (n = 8 in both cases), WIN 55,212-2 strongly favored LTD (n = 7/8) at the apparent expense of LTP (n = 1/8), whereas the opposite effect was observed with SR141716-A (7/8 LTP; 1/8 LTD). These results demonstrate that cannabinoids influence glutamatergic synaptic transmission and plasticity in the PFC of rodent.

Dopamine receptors and groups I and II mGluRs cooperate for long-term depression induction in rat prefrontal cortex through converging postsynaptic activation of MAP kinases.

Tetanic stimuli to layer I-II afferents in rat prefrontal cortex induced long-term depression (LTD) of layer I-II to layer V pyramidal neuron glutamatergic synapses when tetani were coupled to bath application of dopamine. This LTD was blocked by the following metabotropic glutamate receptor (mGluR) antagonists coapplied with dopamine: (S)-alpha-methyl-4-carboxyphenylglycine (MCPG; group I and II antagonist), (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; group I antagonist), or (RS)-alpha-methylserine-O-phosphate monophenyl ester (MSOPPE; group II antagonist). This suggests that the dopamine-facilitated LTD requires synaptic activation of groups I and II mGluRs during tetanus. LTD could also be induced by coupling tetani to bath application of groups I and II mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). In the next series of experiments, coapplication of dopamine and 1S,3R-ACPD, but not application of either drug alone, consistently induced LTD without tetani or even single test stimuli during drug application, suggesting that coactivation of dopamine receptors and the mGluRs is sufficient for LTD induction. Immunoblot analyses with anti-active mitogen-activated protein kinases (MAP-Ks) revealed that D1 receptors, D2 receptors, group I mGluRs, and group II mGluRs all contribute to MAP-K activation in prefrontal cortex, and that combined activation of dopamine receptors and mGluRs synergistically or additively activate MAP-Ks. Consistently, LTD by dopamine + 1S, 3R-ACPD coapplication, as well as the two other forms of LTD (LTD by dopamine + tetani and LTD by 1S,3R-ACPD + tetani), was blocked by bath application of MAP-K kinase inhibitor PD98059. LTD by dopamine + 1S,3R-ACPD coapplication was also blocked by postsynaptic injection of synthetic MAP-K substrate peptide. Our results suggest that dopamine receptors and groups I and II mGluRs cooperate to induce LTD through converging postsynaptic activation of MAP-Ks.

staggerer phenotype in retinoid-related orphan receptor alpha-deficient mice.

Retinoid-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. To study its physiological role we generated null-mutant mice by targeted insertion of a lacZ reporter gene encoding the enzyme beta-galactosidase. In heterozygous RORalpha+/- mice we found beta-galactosidase activity, indicative of RORalpha protein expression, confined to the central nervous system, skin and testis. In the central nervous system, the RORalpha gene is expressed in cerebellar Purkinje cells, the thalamus, the suprachiasmatic nuclei, and retinal ganglion cells. In skin, RORalpha is strongly expressed in the hair follicle, the epidermis, and the sebaceous gland. Finally, the peritubular cells of the testis and the epithelial cells of the epididymis also strongly express RORalpha. Recently, it was reported that the ataxic mouse mutant staggerer (sg/sg) is caused by a deletion in the RORalpha gene. The analysis of the cerebellar and the behavioral phenotype of homozygous RORalpha-/- mice proves identity to sg/sg mice. Although the absence of RORalpha causes dramatic developmental effects in the cerebellum, it has no apparent morphological effect on thalamus, hypothalamus, and retina. Similarly, testis and skin of RORalpha-/- mice display a normal phenotype. However, the pelage hair of both sg/sg and RORalpha-/- is significantly less dense and when shaved shows reluctance to regrow.

Discussion on methods for the evaluation of the personality. Normal brain/damaged brain.

The traditional way for the evaluation of the personality is not always adapted to a brain damaged population. The difficulties encountered by using standardized psychological tests and methods to remedy them are described.

Post-traumatic personality: as many cases as individuals.

Post traumatic personality do not present a unique picture because the disturbances have many causes. That is why models structured basically to the understanding of the disorders must be carried out.

[Neuropsychological and mental profiles in severe post-traumatic diffuse brain lesions. 103 cases]. / Profils neuropsychologiques et mentaux dans les lésions encéphaliques diffuses post-traumatiques sévères. 103 cas.

By studying a series of 103 head severe injured patients who survived and were not vegetative, following post-traumatic diffuse brain damage with clinical signs of axial impairment, the authors stress the importance of using a neuropsychological assessment in order to approach the outcome quality, that the common outcome scales cannot disclose by themselves. They are leading to be careful with regard to the disorders specificity and the merely traumatic origin of sequelae. Moreover they stress the difficulty in predicting the morbidity during the acute stage and only retain the quality of the awake stage and the ventricular size evaluated 3 months following the trauma, as reliable predicting factors. The results point out the disorders heterogeneity observed by that type of head injured patients, despite of the striking constancy of memory defect.