Long term highly saturated fat diet does not induce NASH in Wistar rats

BACKGROUND: Understanding of nonalcoholic steatohepatitis (NASH) is hampered by the lack of a suitable model. Our aim was to investigate whether long term high saturated-fat feeding would induce NASH in rats. METHODS: 21 day-old rats fed high fat diets for 14 weeks, with either coconut oil or butter, and were compared with rats feeding a standard diet or a methionine choline-deficient (MCD) diet, a non physiological model of NASH. RESULTS: MCDD fed rats rapidly lost weight and showed NASH features. Rats fed coconut (86% of saturated fatty acid) or butter (51% of saturated fatty acid) had an increased caloric intake (+143% and +30%). At the end of the study period, total lipid ingestion in term of percentage of energy intake was higher in both coconut (45%) and butter (42%) groups than in the standard (7%) diet group. No change in body mass was observed as compared with standard rats at the end of the experiment. However, high fat fed rats were fattier with enlarged white and brown adipose tissue (BAT) depots, but they showed no liver steatosis and no difference in triglyceride content in hepatocytes, as compared with standard rats. Absence of hepatic lipid accumulation with high fat diets was not related to a higher lipid oxidation by isolated hepatocytes (unchanged ketogenesis and oxygen consumption) or hepatic mitochondrial respiration but was rather associated with a rise in BAT uncoupling protein UCP1 (+25–28% vs standard). CONCLUSION: Long term high saturated fat feeding led to increased "peripheral" fat storage and BAT thermogenesis but did not induce hepatic steatosis and NASH

Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Adaptation du métabolisme hépatique chez le caneton en croissance au froid

Le foie, véritable carrefour métabolique, pourrait participer aux mécanismes adaptatifs que développent les endothermes lors d'exposition prolongée au froid soit directement comme site thermogène soit indirectement en favorisant la fourniture de substrats énergétiques aux tissus thermogènes. Ce travail a étudié les adaptations du métabolisme hépatique chez les canetons de Barbarie en croissance au froid qui développent des capacités de thermogenèse sans frisson (NST, nonshivering thermogenesis) originale en l'absence de tissu adipeux brun, le site majeur de la NST chez les petits mammifères. Deux lots de canetons âgés de 4-5 semaines ont été comparés: des canetons témoins élevés à thermoneutralité (25ʿC, TN) et des canetons acclimatés au froid (4ʿC, AF) pendant 4 semaines. Avec un modèle de foie perfusé, il a été montré que le foie pourrait participer à la thermogenèse de régulation en raison d'une augmentation du métabolisme oxydatif hépatique (+29% à +65%) et de la néoglucogenèse sous contrôle du glucagon (2,2 fois). Avec des hépatocytes isolés, des mécanismes spécifiquement thermogènes n'ont pas été mis en évidence, mais après incubation, les hépatocytes isolés de canetons AF pouvaient montrer une plus forte activité de néoglucogenèse et de cétogenèse. La capacité de lipogenèse hépatique, mesurée par la synthèse de novo des acides gras (AG) et reliée aux activités hépatiques des enzymes clefs de la lipogenèse, était fortement accrue au froid. La lipogenèse hépatique accrue pourrait fournir des substrats lipidiques aux tissus, comme le muscle squelettique, dont le potentiel d'oxydation des AG est accru au froid (+29%). Le foie contribuerait ainsi au maintien de l'équilibre énergétique pendant l'acclimatation au froid en synthétisant des substrats énergétiques indispensables aux tissus thermogènes, cet anabolisme pouvant être générateur de chaleur et participer à la thermogenèse de régulation. La plasticité du métabolisme hépatique après acclimatation au froid pourrait être un élément clef de l'adaptation métabolique au froid de jeunes oiseaux et pourrait contribuer au développement de la NST aviaire. Les particularités du métabolisme hépatique des canetons de Barbarie pourraient contribuer à leur capacité de stéatose bien connue.LYON1-BU.Sciences (692662101) / SudocSudocFranceF

Table_1_Antibiotic Resistance Acquisition in the First Week of Life.XLSX

<p>Objectives: The fetus is considered sterile but recent studies have suggested that gut colonization could start before birth. Scarce data are available for the acquisition of resistant Gram-negative bacteria (GNB) during the first days of life. Several studies have shown that integrons play a major role in antibiotic resistance acquisition. In this work, we studied the dynamics of human intestinal acquisition of GNB and integrons during the first days of life.</p><p>Methods: Meconium was collected at birth and a stool sample before hospital discharge (days 2 or 3) on 185 term neonates. GNB were searched by culture on each sample and class 1, 2, and 3 integrons from each GNB or directly from samples. Eight risk factors for integron and GNB acquisition were studied.</p><p>Results: We isolated 228 GNB, 46 from meconium and the remainder from stools. No link was found between GNB isolation and antibiotic exposure during delivery, but antibiotic exposure during labor significantly selected bla_TEM-positive amoxicillin-resistant Enterobacteria. Two-thirds of GNB were antibiotic-susceptible and most of the resistant isolates were acquired after birth. Integrons were detected in 18 of the 228 GNB isolates from 3 meconium and 20 stools. Antibiotic administration during delivery and vaginal carriage of Streptococcus agalactiae appeared as risk factors for integron acquisition.</p><p>Conclusion: Gram-negative bacteria and integrons are mostly acquired after birth during the first days of life even if for some term neonates, meconium was not sterile. Antibiotic administration during delivery is a major risk for integron acquisition and for selection of amoxicillin-resistant Enterobacteria.</p

Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic diseases. We show here that deletion of one PPARgamma allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPARgamma(+/-) mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARgamma. It is likely that the PPARgamma(+/-) phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPARgamma in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health