Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity.

Autor: Jall S; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Division of Metabolic Diseases, TUM School of Medicine, Technische Universität München, Munich, Germany., De Angelis M; Molecular EXposomics (MEX) at Helmholtz Zentrum München, Neuherberg, Germany., Lundsgaard AM; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Fritzen AM; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Nicolaisen TS; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark., Klein AB; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark., Novikoff A; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Division of Metabolic Diseases, TUM School of Medicine, Technische Universität München, Munich, Germany., Sachs S; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Division of Metabolic Diseases, TUM School of Medicine, Technische Universität München, Munich, Germany.; Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, Neuherberg, Germany., Richter EA; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Kiens B; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Schramm KW; Molecular EXposomics (MEX) at Helmholtz Zentrum München, Neuherberg, Germany.; Department für Biowissenschaften, Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt, Technische Universität München, Freising, Germany., Tschöp MH; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Division of Metabolic Diseases, TUM School of Medicine, Technische Universität München, Munich, Germany.; Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Munich-Neuherberg, Germany., Stemmer K; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Department of Biology, University of Konstanz, Konstanz, Germany., Clemmensen C; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. chc@sund.ku.dk.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany. chc@sund.ku.dk.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark. chc@sund.ku.dk., Müller TD; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. timo.mueller@helmholtz-muenchen.de.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany. timo.mueller@helmholtz-muenchen.de.; Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, Eberhard Karls University Hospitals and Clinics, Tübingen, Germany. timo.mueller@helmholtz-muenchen.de., Kleinert M; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany. maximilian.kleinert@helmholtz-muenchen.de.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany. maximilian.kleinert@helmholtz-muenchen.de.; Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. maximilian.kleinert@helmholtz-muenchen.de.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2020 Jun; Vol. 63 (6), pp. 1236-1247. Date of Electronic Publication: 2020 Mar 06.
DOI: 10.1007/s00125-020-05117-4
Abstrakt: Aims/hypothesis: Treatment with the α3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological and molecular mechanisms are unknown.
Methods: DMPP (10 mg/kg body weight, s.c.) was administered either in a single injection (acute) or daily for up to 14 days (chronic) in DIO wild-type (WT) and Chrnb4 knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucose metabolism, and insulin signalling were assessed.
Results: In WT mice, but not in Chrnb4 KO mice, single acute treatment with DMPP induced transient hyperglycaemia, which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, and decreased hepatic glycogen content. In contrast to these acute effects, chronic DMPP treatment in WT mice elicited improvements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days of DMPP treatment, glucose tolerance was markedly improved, also in comparison with mice that were pair-fed to DMPP-treated mice. The glycaemic benefit of chronic DMPP was absent in Chrnb4 KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue (+69%), heart (+93%), gastrocnemius muscle (+74%) and quadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenaline levels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreased phosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glycogen accumulation following chronic DMPP treatment.
Conclusions/interpretation: Our data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis, while chronic DMPP-mediated activation of β4-containing nAChRs improves peripheral insulin sensitivity independently of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletal muscle.
Databáze: MEDLINE
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