Review. Divergent selection for residual feed intake in the growing pig

To view supplementary material for this article, please visit https:/doi.org/10.1017/S175173111600286XThis review summarizes the results from the INRA (Institut National de la Recherche Agronomique) divergent selection experiment on residual feed intake (RFI) in growing Large White pigs during nine generations of selection. It discusses the remaining challenges and perspectives for the improvement of feed efficiency in growing pigs. The impacts on growing pigs raised under standard conditions and in alternative situations such as heat stress, inflammatory challenges or lactation have been studied. After nine generations of selection, the divergent selection for RFI led to highly significant ( P<0.001) line differences for RFI (−165 g/day in the low RFI (LRFI) line compared with high RFI line) and daily feed intake (−270 g/day). Low responses wereobserved on growth rate (−12.8 g/day, P <0.05) and body composition (+0.9mm backfat thickness, P = 0.57; −2.64% lean meat content, P<0.001) with a marked response on feed conversion ratio (−0.32 kg feed/kg gain, P<0.001). Reduced ultimate pH and increased lightness of the meat ( P<0.001) were observed in LRFI pigs with minor impact on the sensory quality of the meat. These changes in meat quality were associated with changes of the muscular energy metabolism. Reduced maintenance energy requirements (−10% after five generations of selection) and activity (−21% of time standing after six generations of selection) of LRFI pigs greatly contributed to the gain in energy efficiency. However, the impact of selection for RFI on the protein metabolism of the pig remains unclear. Digestibility of energy and nutrients was not affected by selection, neither for pigs fed conventional diets nor for pigs fed high-fibre diets. A significant improvement of digestive efficiency could likely be achieved by selecting pigs on fibre diets. No convincing genetic or blood biomarker has been identified for explaining the differences in RFI, suggesting that pigs have various ways to achieve an efficient use of feed. No deleterious impact of the selection on the sow reproduction performance was observed. The resource allocation theory states that low RFI may reduce the ability to cope with stressors,via the reduction of a buffer compartment dedicated to responses to stress. None of the experiments focussed on the response of pigs to stress or challenges could confirm this theory. Understanding the relationships between RFI and responses to stress and energy demanding processes, as such immunity and lactation, remains a major challenge for a better understanding of the underlying biological mechanisms of the trait and to reconcile the experimental results with the resource allocation theory

The effects of two methods of increasing age at slaughter on carcass and muscle traits and meat sensory quality in pigs

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Effets comparés de deux méthodes d'augmentation de l'âge à l'abattage des porcs sur la composition de la carcasse et des muscles, et la qualité sensorielle de la viande

National audienc

Effets comparés de deux méthodes d'augmentation de l'âge à l'abattage des porcs sur la composition de la carcasse et des muscles, et la qualité sensorielle de la viande

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36èmes journées de la recherche porcine

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Insulin activates hepatic Wnt/β- catenin signaling through stearoyl- CoA desaturase 1 and Porcupine

International audienceThe Wnt/β-catenin pathway plays a pivotal role in liver structural and metabolic homeostasis. Wnt activity is tightly regulated by the acyltransferase Porcupine through the addition of palmitoleate. Interestingly palmitoleate can be endogenously produced by the stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme transcriptionally regulated by insulin. This study aimed to determine whether nutritional conditions, and insulin, regulate Wnt pathway activity in liver. An adenoviral TRE-Luciferase reporter was used as a readout of Wnt/β-catenin pathway activity, in vivo in mouse liver and in vitro in primary hepatocytes. Refeeding enhanced TRE-Luciferase activity and expression of Wnt target genes in mice liver, revealing a nutritional regulation of the Wnt/β-catenin pathway. This effect was inhibited in liver specific insulin receptor KO (iLIRKO) mice and upon wortmannin or rapamycin treatment. Overexpression or inhibition of SCD1 expression regulated Wnt/β-catenin activity in primary hepatocytes. Similarly, palmitoleate added exogenously or produced by SCD1-mediated desaturation of palmitate, induced Wnt signaling activity. Interestingly, this effect was abolished in the absence of Porcupine, suggesting that both SCD1 and Porcupine are key mediators of insulin-induced Wnt/β-catenin activity in hepatocytes. Altogether, our findings suggest that insulin and lipogenesis act as potential novel physiological inducers of hepatic Wnt/β-catenin pathway

Dual regulation of TxNIP by ChREBP and FoxO1 in liver

International audienceTxNIP (Thioredoxin-interacting protein) is considered as a potential drug target for type 2 diabetes. Although TxNIP expression is correlated with hyperglycemia and glucotoxicity in pancreatic β cells, its regulation in liver cells has been less investigated. In the current study, we aim at providing a better understanding of Txnip regulation in hepatocytes in response to physiological stimuli and in the context of hyperglycemia in db/db mice. We focused on regulatory pathways governed by ChREBP (Carbohydrate Responsive Element Binding Protein) and FoxO1 (Forkhead box protein O1), transcription factors that play central roles in mediating the effects of glucose and fasting on gene expression, respectively. Studies using genetically modified mice reveal that hepatic TxNIP is up-regulated by both ChREBP and FoxO1 in liver cells and that its expression strongly correlates with fasting, suggesting a major role for this protein in the physiological adaptation to nutrient restriction

Differential toxicological potential of the main sources contributing to the particle pollution events observed in France

International audienceThe negative impact on health of atmospheric particles (aerosols or particulate matter, PM) at the pulmonary, cardiovascular, and neurological levels is widely recognized. However, the understanding of the PM toxicity emitted from different emission sources and the links with their chemical composition are still poorly known. This is especially the case for sources mainly involved in PM pollution episodes (ie. > 50 µg m-3 of PM10 for several consecutive days). In France, and also in Europe, secondary formation of ammonium nitrate and sulfate (late winter -early spring), biomass burning (in winter, mainly due to residential wood heating), and desert dust (e.g. Saharan dust impacting the French West Indies), account for the main contributors during such episodes (Favez et al., 2021). In such context, the main objective of the SOTOX project is to make a comparison of the toxic potential induced by the predominant sources involved in the episodes of particulate pollution observed in France. Biomass combustion sources (primary emissions) and Saharan dust are therefore targeted in the first place. The originality of the work is to propose a differentiated assessment of the toxic potential of various PM sources based on acellular, biological (cellular in vitro) tests, together with an extensive chemical characterization, using PM samples collected during experiments performed in simulated real-world conditions or in ambient air.A set of PM samples collected on filters (n = 80), through different research projects allowed covering the following PM emissions sources:(a) Primary emissions from residential heating: open fireplace, old (5*) logwood stove, modern (7*) logwood/pellet stoves/boilers, oil boiler; tested under different output conditions (nominal and reduced) and using different wood species (hard and softwood),(b) Garden green waste burning (falling leaves, hedge trimming),(c) Desert dust (Saharan episodes in Martinique).The intrinsic PM toxicological potential (/ µg of PM) has been assessed by measuring different toxicity indicators from filter extracts (organic solvent or artificial pulmonary fluid). The acellular oxidative potential (OP) of the PM was determined using different specific probes (ascorbic acid (AA) and dithiothreitol (DTT)). Oxidative/nitrosative stress induction was investigated on human lung cells (A549) using the H2DCFDA (2′,7′-Dichlorodihydrofluorescein diacetate) probe. A bio-analytical approach based on the measurement of the activation of the AhR receptor (aryl hydrocarbon receptor) in human liver cells (HepG2) exposed to PM extracts permitted to evaluate the content of the particles in dioxin- and HAP-like pollutants. In addition, the analysis of key particulate toxic species (metals, polycyclic aromatic hydrocarbons (PAHs)) and their nitrated and oxygenated derivatives), as well as the PM carbonaceous content (elemental and organic carbon, EC-OC), has been performed to study the links between toxicity indicators and PM chemical composition. Results obtained will be compared in terms of intrinsic PM toxicological potential according to the sources, toxicity indicators and PM chemical composition.This work has been performed within the framework of the SOTOX project funded by the French air quality penalt

Differential toxicological potential of the main sources contributing to the particle pollution events observed in France

International audienceThe negative impact on health of atmospheric particles (aerosols or particulate matter, PM) at the pulmonary, cardiovascular, and neurological levels is widely recognized. However, the understanding of the PM toxicity emitted from different emission sources and the links with their chemical composition are still poorly known. This is especially the case for sources mainly involved in PM pollution episodes (ie. > 50 µg m-3 of PM10 for several consecutive days). In France, and also in Europe, secondary formation of ammonium nitrate and sulfate (late winter -early spring), biomass burning (in winter, mainly due to residential wood heating), and desert dust (e.g. Saharan dust impacting the French West Indies), account for the main contributors during such episodes (Favez et al., 2021). In such context, the main objective of the SOTOX project is to make a comparison of the toxic potential induced by the predominant sources involved in the episodes of particulate pollution observed in France. Biomass combustion sources (primary emissions) and Saharan dust are therefore targeted in the first place. The originality of the work is to propose a differentiated assessment of the toxic potential of various PM sources based on acellular, biological (cellular in vitro) tests, together with an extensive chemical characterization, using PM samples collected during experiments performed in simulated real-world conditions or in ambient air.A set of PM samples collected on filters (n = 80), through different research projects allowed covering the following PM emissions sources:(a) Primary emissions from residential heating: open fireplace, old (5*) logwood stove, modern (7*) logwood/pellet stoves/boilers, oil boiler; tested under different output conditions (nominal and reduced) and using different wood species (hard and softwood),(b) Garden green waste burning (falling leaves, hedge trimming),(c) Desert dust (Saharan episodes in Martinique).The intrinsic PM toxicological potential (/ µg of PM) has been assessed by measuring different toxicity indicators from filter extracts (organic solvent or artificial pulmonary fluid). The acellular oxidative potential (OP) of the PM was determined using different specific probes (ascorbic acid (AA) and dithiothreitol (DTT)). Oxidative/nitrosative stress induction was investigated on human lung cells (A549) using the H2DCFDA (2′,7′-Dichlorodihydrofluorescein diacetate) probe. A bio-analytical approach based on the measurement of the activation of the AhR receptor (aryl hydrocarbon receptor) in human liver cells (HepG2) exposed to PM extracts permitted to evaluate the content of the particles in dioxin- and HAP-like pollutants. In addition, the analysis of key particulate toxic species (metals, polycyclic aromatic hydrocarbons (PAHs)) and their nitrated and oxygenated derivatives), as well as the PM carbonaceous content (elemental and organic carbon, EC-OC), has been performed to study the links between toxicity indicators and PM chemical composition. Results obtained will be compared in terms of intrinsic PM toxicological potential according to the sources, toxicity indicators and PM chemical composition.This work has been performed within the framework of the SOTOX project funded by the French air quality penalt

Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target

International audienceBackground & Aims: Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.Methods: Telomere length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.Results: Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model.Conclusions: Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials.Lay summary: Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides