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1. Regenerating islet-derived protein 3α: A promising therapy for diabetes. Preliminary data in rodents and in humans

Author

Aurélie Le Lay, Erwann Philippe, Fanny Roth, Ana Rodriguez Sanchez-Archidona, Florence Mehl, Jessica Denom, Rashmi Prasad, Olof Asplund, Ola Hansson, Mark Ibberson, Fabrizio Andreelli, Lyse Santoro, Paul Amouyal, Gilles Amouyal, Christian Brechot, Laure Jamot, Céline Cruciani-Guglielmacci, and Christophe Magnan

Subjects
Insulin resistance, Glucose uptake, Skeletal muscles, Type 2 diabetes, Science (General), Q1-390, Social sciences (General), H1-99
Abstract

The aim of our study was to test the hypothesis that administration of Regenerating islet-derived protein 3α (Reg3α), a protein described as having protective effects against oxidative stress and anti-inflammatory activity, could participate in the control of glucose homeostasis and potentially be a new target of interest in the treatment of type 2 diabetes. To that end the recombinant human Reg3α protein was administered for one month in insulin-resistant mice fed high fat diet. We performed glucose and insulin tolerance tests, assayed circulating chemokines in plasma and measured glucose uptake in insulin sensitive tissues. We evidenced an increase in insulin sensitivity during an oral glucose tolerance test in ALF-5755 treated mice vs controls and decreased the pro-inflammatory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5). We also demonstrated an increase in glucose uptake in skeletal muscle. Finally, correlation studies using human and mouse muscle biopsies showed negative correlation between intramuscular Reg3α mRNA expression (or its murine isoform Reg3γ) and insulin resistance. Thus, we have established the proof of concept that Reg3α could be a novel molecule of interest in the treatment of T2D by increasing insulin sensitivity via a skeletal muscle effect.

Published
2022
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2. Portal Glucose Infusion, Afferent Nerve Fibers, and Glucose and Insulin Tolerance of Insulin-Resistant Rats

Author

Aurélie Joly-Amado, Maud Soty, Erwann Philippe, Amelie Lacombe, Julien Castel, Bruno Pillot, Justine Vily-Petit, Carine Zitoun, Gilles Mithieux, Christophe Magnan, 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 (UPCité), Nutrition, diabète et cerveau (NUDICE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), and Di Carlo, Marie-Ange

Subjects
Blood Glucose, Male, Nutrition and Dietetics, Portal Vein, sensory nerves, Medicine (miscellaneous), rats, Glucose, Nerve Fibers, high-fat diet, Liver, Insulin, Regular, Human, insulin resistance, hepatoportal glucose sensor, Animals, Insulin, Emulsions, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Capsaicin, Rats, Wistar, Triglycerides
Abstract

International audience; ABSTRACT Background The role of hepatoportal glucose sensors is poorly understood in the context of insulin resistance. Objectives We assessed the effects of glucose infusion in the portal vein on insulin tolerance in 2 rat models of insulin resistance, and the role of capsaicin sensitive nerves in this signal. Methods Male Wistar rats, 8 weeks old, weighing 250–275 g, were used. Insulin and glucose tolerance were assessed following a 4-hour infusion of either glucose or saline through catheterization in the portal vein in 3 paradigms. In experiment 1, for diet-induced insulin resistance, rats were fed either a control diet (energy content: proteins = 22.5%, carbohydrates = 64.1%, and lipids = 13.4%) or a high-fat diet (energy content: proteins = 15.3%, carbohydrates = 40.3%, and lipids =44.4%) for 4 months. In experiment 2, for centrally induced peripheral insulin resistance, catheters were inserted in the carotid artery to deliver either an emulsion of triglycerides [intralipid (IL)] or saline towards the brain for 24 hours. In experiment 3, for testing the role of capsaicin-sensitive nerves, experiment 2 was repeated following a periportal treatment with capsaicin or vehicle. Results In experiment 1, when compared to rats fed the control diet, rats fed the high-fat diet exhibited decreased insulin and glucose tolerance (P ≤ 0.05) that was restored with a glucose infusion in the portal vein (P ≤ 0.05). In experiment 2, infusion of a triglyceride emulsion towards the brain (IL rats) decreased insulin and glucose tolerance and increased hepatic endogenous production when compared to saline-infused rats (P ≤ 0.05). Glucose infusion in the portal vein in IL rats restored insulin and glucose tolerance, as well as hepatic glucose production, to controls levels (P ≤ 0.05). In experiment 3, portal infusion of glucose did not increase insulin tolerance in IL rats that received a periportal pretreatment with capsaicin. Conclusions Stimulation of hepatoportal glucose sensors increases insulin tolerance in rat models of insulin resistance and requires the presence of capsaicin-sensitive nerves.

Published
2022
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3. Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions

Author

Erwann Philippe, Athanassia Sotiropoulos, Hervé Le Stunff, Agnieszka Blachnio-Zabielska, Julien Véret, Paola Giussani, Fabienne Foufelle, Cécile L Bandet, Maxime Poirier, Xavier Le Liepvre, Olivier Bourron, Pascal Ferré, Eric Hajduch, Raphaëlle Ballaire, Jan Górski, Dušan Berkeš, Rana Mahfouz, Mélanie Campana, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pathogenèse cellulaire et clinique du diabète (CRC - Inserm U1138), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Nutrition, diabète et cerveau, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Bialystok Med Univ, Virologie et Immunologie Moléculaire, Faculté des Sciences Pharmaceutiques, Institut National de la Recherche Agronomique (INRA)-Université Francois Rabelais [Tours], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Slovak University of Technology in Bratislava, Department of Physiology, Medical University of Bialystok, Pathologies nutritionnelles et métaboliques : obésité et diabète, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 Diderot - Paris 7 (UPD7), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Medical University of Białystok (MUB), Service de Diabétologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hajduch, Eric, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Adult, Male, Ceramide, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Golgi Apparatus, Mice, Transgenic, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Protein Serine-Threonine Kinases, Ceramides, Endoplasmic Reticulum, 03 medical and health sciences, chemistry.chemical_compound, Mice, Insulin resistance, Internal Medicine, medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Myocyte, Animals, Humans, Insulin, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, biology, Muscles, Fatty Acids, medicine.disease, Sphingolipid, Cell biology, Mice, Inbred C57BL, Insulin receptor, 030104 developmental biology, chemistry, Lipotoxicity, biology.protein, Signal transduction, Insulin Resistance, Signal Transduction
Abstract

International audience; One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid-induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase-dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process.

Published
2018
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4. The Zinc Transporter Slc30a8/ZnT8 Is Required in a Subpopulation of Pancreatic α-Cells for Hypoglycemia-induced Glucagon Secretion

Author

Christophe Magnan, Stéphanie Migrenne Li, Guy A. Rutter, Elisa A. Bellomo, Erwann Philippe, Alejandra Tomas, Pedro Luis Herrera, David J. Hodson, Antonia Solomou, Gargi Meur, and Medical Research Council (MRC)

Subjects
Biochemistry, 0302 clinical medicine, Glucose homeostasis, ddc:576.5, Cation Transport Proteins, IN-VIVO, Cells, Cultured, 0303 health sciences, geography.geographical_feature_category, diabetes, SLC30A8, digestive, oral, and skin physiology, zinc, Glucagon secretion, 11 Medical And Health Sciences, Islet, 3. Good health, secretion, ISLETS, Zinc Transporter 8, Female, 03 Chemical Sciences, Life Sciences & Biomedicine, hormones, hormone substitutes, and hormone antagonists, EXPRESSION, endocrine system, Biochemistry & Molecular Biology, medicine.medical_specialty, 030209 endocrinology & metabolism, Biology, Hypoglycemia, INSULIN-SECRETION, Glucagon, 03 medical and health sciences, BETA-CELLS, Insulin resistance, Internal medicine, medicine, Animals, GENOME-WIDE ASSOCIATION, Molecular Biology, 030304 developmental biology, RELEASE, FREE CYTOSOLIC ZN2+, geography, Science & Technology, calcium, Cell Biology, 06 Biological Sciences, medicine.disease, RISK LOCI, Mice, Inbred C57BL, Metabolism, Glucose, Endocrinology, Glucagon-Secreting Cells, biology.protein, GLUCOSE-HOMEOSTASIS, Insulin Resistance, Gene Deletion
Abstract

Background: The role of the type 2 diabetes risk gene SLC30A8, encoding ZnT8, in the control of glucagon secretion is not clearly established. Results: Inactivation of ZnT8 in a subset of α-cells leads to increased glucagon secretion in vivo and in vitro. Conclusion: ZnT8 is involved in normal glucagon release. Significance: SLC30A8 diabetes risk alleles may influence glucagon secretion., SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of Slc30a8 in the control of glucagon secretion, Slc30a8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP+: glucagon+ cells from KO mice, revealed recombination in ∼30% of α-cells, of which ∼50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn2+ levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca2+ increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca2+-independent mechanisms.

Published
2015
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5. Lipoprotein lipase in hypothalamus is a key regulator of body weight gain and glucose homeostasis in mice

Author

Xavier Fioramonti, Valentine S. Moullé, Robert H. Eckel, Nadim Kassis, Charlotte Vanacker, Kimberley D. Bruce, Hervé Le Stunff, Cristina García-Cáceres, Erwann Philippe, Chloé Berland, Benoit Colsch, Noémie Butin, Elise Laperrousaz, Yuanqing Gao, Matthias H. Tschöp, Vincent Prévot, Amélie Lacombe, Hong Wang, Serge Luquet, Yongping Wang, Christophe Magnan, Raphael G. P. Denis, Céline Cruciani-Guglielmacci, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Munich Cancer Registry of the Munich Cancer Center, Department of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität München (LMU), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, University of Colorado Anschutz [Aurora], European Foundation for Study of Diabetes (EFSD/Lilly Research Fellowship Programme), ANR: Lipobrain,ANR SVSE 1 2011 Lipobrain, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, ANR-11-BSV1-0021,lipobrain,Rôle de la lipoprotéine lipase dans le contrôle nerveux de la balance énergétique(2011), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Biologie Fonctionnelle et Adaptative ( BFA ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Ludwig-Maximilians-Universität München, Laboratoire de génie chimique, UMR 5503 (CNRS/INPT/UPS), Département Bioprocédés et Systèmes Microbiens, UPS-INPT-Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, University of Colorado Denver School of Medicine [Aurora, CO, USA], and ANR : Lipobrain,ANR SVSE 1 2011 Lipobrain

Subjects
Male, 0301 basic medicine, Time Factors, nervous-system, hippocampus, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Diabetes and Metabolism, neurons, Weight Gain, Energy homeostasis, Mice, chemistry.chemical_compound, Homeostasis, Glucose homeostasis, Glucose tolerance test, Lipoprotein lipase, medicine.diagnostic_test, Hydrolysis, Dependovirus, Lipids, energy-balance, Phenotype, Hypothalamus, Body Composition, lipids (amino acids, peptides, and proteins), diabetes-mellitus, Ceramide, medicine.medical_specialty, diet-induced obesity, brain, Green Fluorescent Proteins, Mice, Transgenic, Calorimetry, Biology, Ceramides, Triacylglycerol, insulin-resistance, 03 medical and health sciences, Insulin resistance, Internal medicine, Internal Medicine, medicine, Animals, Obesity, Nutrient utilisation, Triglycerides, Body Weight, nutritional and metabolic diseases, Glucose Tolerance Test, medicine.disease, gene-expression, Mice, Inbred C57BL, Glucose, 030104 developmental biology, Endocrinology, chemistry, metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Gene Deletion
Abstract

International audience; Aims/hypothesis Regulation of energy balance involves the participation of many factors, including nutrients, among which are circulating lipids, acting as peripheral signals informing the central nervous system of the energy status of the organism. It has been shown that neuronal lipoprotein lipase (LPL) participates in the control of energy balance by hydrolysing lipid particles enriched in triacylglycerols. Here, we tested the hypothesis that LPL in the mediobasal hypothalamus (MBH), a well-known nucleus implicated in the regulation of metabolic homeostasis, could also contribute to the regulation of body weight and glucose homeostasis.Methods We injected an adeno-associated virus (AAV) expressing Cre-green fluorescent protein into the MBH of Lpl-floxed mice (and wild-type mice) to specifically decrease LPL activity in the MBH. In parallel, we injected an AAV overexpressing Lpl into the MBH of wild-type mice. We then studied energy homeostasis and hypothalamic ceramide content.Results The partial deletion of Lpl in the MBH in mice led to an increase in body weight compared with controls (37.72 +/- 0.7 g vs 28.46 +/- 0.12, p < 0.001) associated with a decrease in locomotor activity. These mice developed hyperinsulinaemia and glucose intolerance. This phenotypealso displayed reduced expression of Cers1 in the hypothalamus as well as decreased concentration of several C18 species of ceramides and a 3-fold decrease in total ceramide intensity. Conversely, overexpression of Lpl specifically in the MBH induced a decrease in body weight.Conclusions/interpretation Our study shows that LPL in the MBH is an important regulator of body weight and glucose homeostasis.

Published
2017
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6. Dietary supplementation withAgaricus blazeimurill extract prevents diet-induced obesity and insulin resistance in rats

Author

Yorihiko Takeda, Mylène Vincent, Claude Rouch, Nadim Kassis, Patrice D. Cani, Shoji Uchiyama, Stéphanie Migrenne, Christophe Magnan, Nathalie M. Delzenne, Erwann Philippe, Jessica Denom, and Amandine Everard

Subjects
medicine.medical_specialty, Nutrition and Dietetics, Intra-Abdominal Fat, biology, business.industry, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, Inflammation, Gut flora, medicine.disease, biology.organism_classification, Obesity, Jejunum, Endocrinology, Insulin resistance, medicine.anatomical_structure, Internal medicine, medicine, medicine.symptom, business, Weight gain
Abstract

Dietary supplement may potentially help to fight obesity and other metabolic disorders such as insulin-resistance and low-grade inflammation. The present study aimed to test whether supplementation with Agaricus blazei murill (ABM) extract could have an effect on diet-induced obesity in rats. Wistar rats were fed with control diet (CD) or high-fat diet (HF) and either with or without supplemented ABM for 20 weeks. HF diet-induced body weight gain and increased fat mass compared to CD. In addition HF-fed rats developed hyperleptinemia and insulinemia as well as insulin resistance and glucose intolerance. In HF-fed rats, visceral adipose tissue also expressed biomarkers of inflammation. ABM supplementation in HF rats had a protective effect against body weight gain and all study related disorders. This was not due to decreased food intake which remained significantly higher in HF rats whether supplemented with ABM or not compared to control. There was also no change in gut microbiota composition in HF supplemented with ABM. Interestingly, ABM supplementation induced an increase in both energy expenditure and locomotor activity which could partially explain its protective effect against diet-induced obesity. In addition a decrease in pancreatic lipase activity is also observed in jejunum of ABM-treated rats suggesting a decrease in lipid absorption. Taken together these data highlight a role for ABM to prevent body weight gain and related disorders in peripheral targets independently of effect in food intake in central nervous system.

Published
2013
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7. Dietary Supplementation With Agaricus Blazei Murill Extract Prevents Diet-Induced Obesity and Insulin Resistance in Rats

Author

Mylène Vincent, Erwann Philippe, Amandine Everard, Nadim Kassis, Claude Rouch, Jessica Denom, Yorihiko Takeda, Shoji Uchiyama, Nathalie M. Delzenne, Patrice D. Cani, Stéphanie Migrenne, and Christophe Magnan

Subjects
Blood Glucose, Leptin, Male, Agaricus, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Intra-Abdominal Fat, Diet, High-Fat, Weight Gain, Endocrinology, Glucose Intolerance, Animals, Insulin, Obesity, Rats, Wistar, Inflammation, Nutrition and Dietetics, Microbiota, Probiotics, Calorimetry, Indirect, Lipase, Dietary Fats, Subcutaneous Fat, Abdominal, Rats, Gastrointestinal Tract, Dietary Supplements, Body Composition, Insulin Resistance, Energy Metabolism, Biomarkers
Abstract

Dietary supplement may potentially help to fight obesity and other metabolic disorders such as insulin-resistance and low-grade inflammation. The present study aimed to test whether supplementation with Agaricus blazei murill (ABM) extract could have an effect on diet-induced obesity in rats.Wistar rats were fed with control diet (CD) or high-fat diet (HF) and either with or without supplemented ABM for 20 weeks.HF diet-induced body weight gain and increased fat mass compared to CD. In addition HF-fed rats developed hyperleptinemia and insulinemia as well as insulin resistance and glucose intolerance. In HF-fed rats, visceral adipose tissue also expressed biomarkers of inflammation. ABM supplementation in HF rats had a protective effect against body weight gain and all study related disorders. This was not due to decreased food intake which remained significantly higher in HF rats whether supplemented with ABM or not compared to control. There was also no change in gut microbiota composition in HF supplemented with ABM. Interestingly, ABM supplementation induced an increase in both energy expenditure and locomotor activity which could partially explain its protective effect against diet-induced obesity. In addition a decrease in pancreatic lipase activity is also observed in jejunum of ABM-treated rats suggesting a decrease in lipid absorption.Taken together these data highlight a role for ABM to prevent body weight gain and related disorders in peripheral targets independently of effect in food intake in central nervous system.

Published
2012
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