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1. Filarial DAF-12 sense the host serum to resume iL3 development during infection.

Author

Rémy Bétous, Anthony Emile, Hua Che, Eva Guchen, Didier Concordet, Thavy Long, Sandra Noack, Paul M Selzer, Roger Prichard, and Anne Lespine

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Nematode parasites enter their definitive host at the developmentally arrested infectious larval stage (iL3), and the ligand-dependent nuclear receptor DAF-12 contributes to trigger their development to adulthood. Here, we characterized DAF-12 from the filarial nematodes Brugia malayi and Dirofilaria immitis and compared them with DAF-12 from the non-filarial nematodes Haemonchus contortus and Caenorhabditis elegans. Interestingly, Dim and BmaDAF-12 exhibit high sequence identity and share a striking higher sensitivity than Hco and CelDAF-12 to the natural ligands Δ4- and Δ7-dafachronic acids (DA). Moreover, sera from different mammalian species activated specifically Dim and BmaDAF-12 while the hormone-depleted sera failed to activate the filarial DAF-12. Accordingly, hormone-depleted serum delayed the commencement of development of D. immitis iL3 in vitro. Consistent with these observations, we show that spiking mouse charcoal stripped-serum with Δ4-DA at the concentration measured in normal mouse serum restores its capacity to activate DimDAF-12. This indicates that DA present in mammalian serum participate in filarial DAF-12 activation. Finally, analysis of publicly available RNA sequencing data from B. malayi showed that, at the time of infection, putative gene homologs of the DA synthesis pathways are coincidently downregulated. Altogether, our data suggest that filarial DAF-12 have evolved to specifically sense and survive in a host environment, which provides favorable conditions to quickly resume larval development. This work sheds new light on the regulation of filarial nematodes development while entering their definitive mammalian host and may open the route to novel therapies to treat filarial infections.

Published
2023
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2. When translation elongation is impaired, the mRNA is uniformly destabilized by the RNA degradosome, while the concentration of mRNA is altered along the molecule

Author

Marie-Pierre Duviau, Fan Chen, Anthony Emile, Muriel Cocaign-Bousquet, Laurence Girbal, Sébastien Nouaille, Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

mRNA sits at the crossroads of transcription, translation and mRNA degradation. Many questions remain about the coupling of these three processes in Escherichia coli and, in particular, how translation may have an effect on mRNA degradation and transcription. To characterize the interplay between mRNA degradation and translation while accounting for transcription, we altered the translation initiation or elongation and measured the effects on mRNA stability and concentration. Using a mapping method, we analysed mRNA concentration and stability at the local scale all along the transcript. We showed that a decrease in translation initiation efficiency destabilizes the mRNA and leads to a uniform decrease in mRNA concentration throughout the molecule. Prematurely terminating translation elongation by inserting a stop codon is associated with a drop in local mRNA concentration downstream of the stop codon, due to the uncoupling of transcription and translation. In contrast, this translation alteration uniformly destabilizes the coding and ribosome-free regions, in a process triggered by RNase E activity, and its ability to form the RNA degradome. These results demonstrate how ribosomes protect mRNA molecules and highlight how translation, mRNA degradation and transcription are deeply interconnected in the quality control process that avoids unproductive gene expression in cells.

Published
2023
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3. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

Author

Anne Fougerat, Gabriele Schoiswohl, Arnaud Polizzi, Marion Régnier, Carina Wagner, Sarra Smati, Tiffany Fougeray, Yannick Lippi, Frederic Lasserre, Ilyès Raho, Valentine Melin, Blandine Tramunt, Raphaël Métivier, Caroline Sommer, Fadila Benhamed, Chantal Alkhoury, Franziska Greulich, Céline Jouffe, Anthony Emile, Michael Schupp, Pierre Gourdy, Patricia Dubot, Thierry Levade, Delphine Meynard, Sandrine Ellero-Simatos, Laurence Gamet-Payrastre, Ganna Panasyuk, Henriette Uhlenhaut, Ez-Zoubir Amri, Céline Cruciani-Guglielmacci, Catherine Postic, Walter Wahli, Nicolas Loiseau, Alexandra Montagner, Dominique Langin, Achim Lass, Hervé Guillou, Graz University of Technology [Graz] (TU Graz), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Transcriptomic impact of Xenobiotics (E23 TRiX), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Santé Digestive (IRSD ), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), German Research Center for Environmental Health - Helmholtz Center München (GmbH), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Nanyang Technological University [Singapour], University of Lausanne (UNIL), BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität [Graz, Autriche]-Medical University Graz, Région Occitanie, FRM (FDM201906008682), Boulos Foundation, ERC-2018-COG-MetaboSENS-819543, German Research Foundation (DFG) (SCH 2546/5-1), the Leuchtturmprojekt/Flagship Project 'Lipases and Lipid Signaling' funded by BioTechMed-Graz, ANR-16-CE14-0029,NUTRISENSPIK,Déterminants moléculaires de l'homéostasie hépatique nutritive(2016), ANR-17-CE14-0015,HepAdialogue,Impact du métabolisme des acides gras des tissus adipeux et du foie sur l'insulinorésistance(2017), ANR-21-CE14-0079,Hepatologic,Réseau de controle des réponses transcriptionnelles hépatiques aux challenges nutritionnels par des récepteurs nucléaires(2021), European Project: 267196,EC:FP7:PEOPLE,FP7-PEOPLE-2010-COFUND,AGREENSKILLS(2012), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Medical University of Graz, Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Diabétologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Helmholtz Zentrum München = German Research Center for Environmental Health, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lee Kong Chian School of Medicine, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Technische Universität Graz (TU Graz), Région Occitanie B.T. was supported by FRM (FDM201906008682)., Boulos Foundation and FRM., German Research Foundation (DFG) (SCH 2546/5-1 to M.S.), I3535, andP34899 (A.L.) by Austrian Science Fund (FWF, ERC-2018-COG-MetaboSENS- 819543 (G.P.), the Leuchtturmprojekt/Flagship Project ‘‘Lipases and Lipid Signaling’’ (A.L.), funded by BioTechMed-Graz, and by P28882-B21 (G.S.), European Project: 609398,EC:FP7:PEOPLE,FP7-PEOPLE-2013-COFUND,AGREENSKILLSPLUS(2014), Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, LESUR, Hélène, Impact du métabolisme des acides gras des tissus adipeux et du foie sur l'insulinorésistance - - HepAdialogue2017 - ANR-17-CE14-0015 - AAPG2017 - VALID, Réseau de controle des réponses transcriptionnelles hépatiques aux challenges nutritionnels par des récepteurs nucléaires - - Hepatologic2021 - ANR-21-CE14-0079 - AAPG2021 - VALID, Déterminants moléculaires de l'homéostasie hépatique nutritive - - NUTRISENSPIK2016 - ANR-16-CE14-0029 - AAPG2016 - VALID, and AgreenSkills+ - AGREENSKILLSPLUS - - EC:FP7:PEOPLE2014-05-05 - 2019-05-04 - 609398 - VALID

Subjects
fasting, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Adipose Tissue, White, Metabolism, Fgf21, Pparα, Fasting, Ketogenesis, Lipolysis [Atgl, Cp], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Ketone Bodies, [SDV.TOX.TCA]Life Sciences [q-bio]/Toxicology/Toxicology and food chain, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, PPARα, General Biochemistry, Genetics and Molecular Biology, ATGL, FGF21, Adipose Tissue, Brown, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], PPAR alpha, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, CP: Metabolism, ketogenesis, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Adipose Tissue, Hepatocytes, lipolysis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; In hepatocytes, peroxisome proliferator-activated receptor α (PPARα) orchestrates a genomic and metabolic response required for homeostasis during fasting. This includes the biosynthesis of ketone bodies and of fibroblast growth factor 21 (FGF21). Here we show that in the absence of adipose triglyceride lipase (ATGL) in adipocytes, ketone body and FGF21 production is impaired upon fasting. Liver gene expression analysis highlights a set of fasting-induced genes sensitive to both ATGL deletion in adipocytes and PPARα deletion in hepatocytes. Adipose tissue lipolysis induced by activation of the β3-adrenergic receptor also triggers such PPARα-dependent responses not only in the liver but also in brown adipose tissue (BAT). Intact PPARα activity in hepatocytes is required for the cross-talk between adipose tissues and the liver during fat mobilization.

Published
2022
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4. ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

Author

Marion Régnier, Ganna Panasyuk, Michael Schupp, Yannick Lippi, Arnaud Polizzi, Chantal Alkhoury, Tiffany Fougeray, Patricia Dubot, Anne Fougerat, Sarra Smati, Anthony Emile, Gabriele Schoiswohl, Laurence Gamet-Payrastre, Carina Wagner, Valentine Melin, Catherine Postic, Nicolas Loiseau, Blandine Tramunt, Sandrine Ellero-Simatos, Ez-Zoubir Amri, Walter Wahli, Achim Lass, Dominique Langin, Alexandra Montagner, Hervé Guillou, Pierre Gourdy, Thierry Levade, and Frédéric Lasserre

Subjects
medicine.medical_specialty, FGF21, Adipose tissue, White adipose tissue, chemistry.chemical_compound, Endocrinology, medicine.anatomical_structure, chemistry, Adipocyte, Internal medicine, Hepatocyte, Adipose triglyceride lipase, Brown adipose tissue, medicine, Lipolysis
Abstract

ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor α (PPARα) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPARα has not been investigated.MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPARα. Finally, we tested the consequences of hepatocyte-specific PPARα deficiency during pharmacological induction of adipocyte lipolysis with a β3-adrenergic receptor agonist.ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPARα target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPARα. Adipose tissue lipolysis induced by acute activation of the β3-adrenergic receptor also triggered PPARα-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPARα activity. In addition, the absence of hepatocyte PPARα altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the β3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPARα showed decreased tolerance to acute cold exposure.ConclusionsThese results underscore the central role of hepatocyte PPARα in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPARα activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.

Published
2021
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5. The new natural law theory and the question of same -sex marriage

Author

Giampietro, Anthony Emile and Giampietro, Anthony Emile

Abstract

In this dissertation I engage the new natural law argument that homosexual acts cannot be marital acts. I address two important disputes within contemporary philosophy. One is the issue of whether or not the new natural law approach is an authentic natural law approach. The other is whether or not this approach is adequate to the task of calling into question the arguments of those who advocate that persons of the same sex be given the legal right to marry one another. I argue further that these two disputes are related, that is, that the question of whether the new natural law theory is really a natural law theory has a direct impact on the question of its adequacy in dealing with the question of same-sex marriage. The core of my argument is that the lack of an explicit metaphysics undermines both the natural law argument and the arguments of some who advocate same-sex marriage. I argue that the new natural law view ought not be taken lightly, however, since the intuition that it depends upon, namely, that the union-effecting nature of heterosexual intercourse is essential to the meaning of marriage, has wide support. But while this intuition may indeed be a recognition of a moral truth, the new natural lawyers do not show this to be the case. I then address the fact that many arguments for same-sex marriage depend upon the presupposition that sexual activity in general is in some sense union-effecting. I suggest that this presupposition is unwarranted and that it depends upon an acceptance and transference of the union-effecting meaning that the new natural lawyers say is intrinsic only to heterosexual intercourse and not to other kinds of sexual acts. In my conclusion I offer some suggestions for future work on this issue, specifically in the area of the metaphysics, or the nature, of sexual acts.

Published
2003

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