Neuraminidase 1 activates insulin receptor and reverses insulin resistance in obese mice
| Autor: | Jeffrey A. Medin, Xuefang Pan, Victoria Smutova, Bruno Larrivée, Christopher W. Cairo, Nikolaus Heveker, Anne Fougerat, Alexey V. Pshezhetsky, Tarik Issad |
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| Přispěvatelé: | Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Research center, Ste-Justine Hospital Research Center, 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), Angiogénèse embryonnaire et pathologique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Biophysics (MBP), University of Toronto, Division of Medical Genetics, CHU Sainte Justine [Montréal], Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Labex MemoLife, Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC) |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
HFD high-fat diet medicine.medical_treatment PNA peanut agglutinin IGTT intraperitoneal glucose tolerance test Cathepsin A Mice NEU1 0302 clinical medicine TFEB transcription factor EB Receptor DANA 2 3-dehydro-2-deoxy-N-acetylneuraminic acid AV adenovirus LV lentivrus ComputingMilieux_MISCELLANEOUS PA palmitate Ambroxol trans-4-(2-Amino-3 5-dibromobenzylamino)cyclohexanol biology Chemistry Hep G2 Cells [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism 3. Good health Insulin signaling Ambroxol Liver IR insulin receptor Original Article lcsh:Internal medicine medicine.medical_specialty Neuraminidase 03 medical and health sciences Insulin resistance Neuraminidase 1 Internal medicine medicine Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Obesity BRET bioluminescence resonance energy transfer Muscle Skeletal lcsh:RC31-1245 Molecular Biology ITT insulin tolerance test Activator (genetics) Catabolism NEU1 neuraminidase 1 Insulin T2DM type 2 diabetes mellitus Cell Biology medicine.disease Receptor Insulin Mice Inbred C57BL Insulin receptor HEK293 Cells 030104 developmental biology Endocrinology biology.protein [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology 030217 neurology & neurosurgery |
| Zdroj: | Molecular Metabolism, Vol 12, Iss, Pp 76-88 (2018) Molecular metabolism Molecular metabolism, Elsevier, 2018, 12, pp.76-88. ⟨10.1016/j.molmet.2018.03.017⟩ Molecular Metabolism |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2018.03.017 |
| Popis: | Objectives Neuraminidase 1 (NEU1) cleaves terminal sialic acids of glycoconjugates during lysosomal catabolism. It also modulates the structure and activity of cellular surface receptors affecting diverse pathways. Previously we demonstrated that NEU1 activates the insulin receptor (IR) and that NEU1-deficient CathAS190A-Neo mice (hypomorph of the NEU1 activator protein, cathepsin A/CathA) on a high-fat diet (HFD) develop hyperglycaemia and insulin resistance faster than wild-type animals. The major objective of the current work was to reveal the molecular mechanism by which NEU1 desialylation activates the IR and to test if increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance. Methods To test if desialylation causes a conformational change in the IR dimer we measured interaction between the receptor subunits by Bioluminescence Resonance Energy Transfer in the HEK293T cells either overexpressing NEU1 or treated with the NEU1 inhibitor. The influence of NEU1 overexpression on insulin resistance was studied in vitro in palmitate-treated HepG2 cells transduced with NEU1-expressing lentivirus and in vivo in C57Bl6 mice treated with HFD and either pharmacological inducer of NEU1, Ambroxol or NEU1-expressing adenovirus. NEU1-deficient CathAS190A-Neo mice were used as a control. Results By desialylation of IR, NEU1 induced formation of its active dimer leading to insulin signaling. Overexpression of NEU1 in palmitate-treated HepG2 cells restored insulin signaling, suggesting that increased NEU1 levels may reverse insulin resistance. Five-day treatment of glycemic C57Bl6 mice receiving HFD with the activator of the lysosomal gene network, Ambroxol, increased NEU1 expression and activity in muscle tissue, normalized fasting glucose levels, and improved physiological and molecular responses to glucose and insulin. Ambroxol did not improve insulin sensitivity in obese insulin-resistant CathAS190A-Neo mice indicating that the Ambroxol effect is mediated through NEU1 induction. Sustained increase of liver NEU1 activity through adenovirus-based gene transfer failed to attenuate insulin resistance most probably due to negative feedback regulation of IR expression. Conclusion Together our results demonstrate that increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance suggesting that a pharmacological modulation of NEU1 activity may be potentially explored for restoring insulin sensitivity and resolving hyperglycemia associated with T2DM. Highlights • Desialylation of insulin receptor by NEU1 induces formation of its active dimer leading to insulin signaling. • Overexpression of NEU1 in palmitate-treated HepG2 cells restores insulin signaling. • Acute treatment with Ambroxol reverses insulin resistance and glycemia in high-fat diet mouse model. • Ambroxol effect is mediated through NEU1 induction. • Pharmacological modulation of NEU1 activity may be potentially explored for treatment of insulin resistance. |
| Databáze: | OpenAIRE |
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