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

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2020

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Jall, Sigrid
De Angelis, Meri
Lundsgaard, Anne-Marie
Fritzen, Andreas M.
Nicolaisen, Trine S.
Klein, Anders B.
Clemmensen, Christoffer
Müller, Timo D.
Kleinert, Maximilian
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Diabetologia. Springer. 2020, 63(6), pp. 1236-1247. ISSN 0012-186X. eISSN 1432-0428. Available under: doi: 10.1007/s00125-020-05117-4

Zusammenfassung

ims/hypothesisTreatment with theα3β4 nicotinic acetylcholine receptor (nAChR) agonist, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), improves glucose tolerance in diet-induced obese (DIO) mice, but the physiological andmolecular mechanisms are unknown.MethodsDMPP (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) andChrnb4knockout (KO) mice and glucose tolerance, tissue-specific tracer-based glucosemetabolism, and insulin signalling were assessed.ResultsIn WT mice, but not inChrnb4KO mice, single acute treatment with DMPP induced transient hyperglycaemia,which was accompanied by high plasma adrenaline (epinephrine) levels, upregulated hepatic gluconeogenic genes, anddecreased hepatic glycogen content. In contrast to theseacute effects, chronic DMPP treatment in WT mice elicitedimprovements in glucose tolerance already evident after three consecutive days of DMPP treatment. After seven days ofDMPP treatment, glucose tolerance was markedly improved,alsoincomparisonwithmicethatwerepair-fedtoDMPP-treated mice. The glycaemic benefit of chronic DMPP was absent inChrnb4KO mice. Chronic DMPP increased insulin-stimulated glucose clearance into brown adipose tissue(+69%), heart (+93%), gastrocnemius muscle (+74%) andquadriceps muscle (+59%), with no effect in white adipose tissues. After chronic DMPP treatment, plasma adrenalinelevels did not increase following an injection with DMPP. In glucose-stimulated skeletal muscle, we detected a decreasedphosphorylation of the inhibitory Ser640 phosphorylation site on glycogen synthase and a congruent increase in glyco-gen accumulation following chronic DMPP treatment.Conclusions/interpretationOur data suggest that DMPP acutely induces adrenaline release and hepatic glycogenolysis,while chronic DMPP-mediated activation ofβ4-containing nAChRs improves peripheral insulin sensitivity independent-ly of changes in body weight via mechanisms that could involve increased non-oxidative glucose disposal into skeletalmuscle.

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Fachgebiet (DDC)
570 Biowissenschaften, Biologie

Schlagwörter

Catecholamine, Glucose metabolism, Glucose tolerance, Hyperglycaemia, Insulin sensitivity, Nicotinicacetylcholine receptor, Pharmacology

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ISO 690JALL, Sigrid, Meri DE ANGELIS, Anne-Marie LUNDSGAARD, Andreas M. FRITZEN, Trine S. NICOLAISEN, Anders B. KLEIN, Kerstin STEMMER, Christoffer CLEMMENSEN, Timo D. MÜLLER, Maximilian KLEINERT, 2020. Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity. In: Diabetologia. Springer. 2020, 63(6), pp. 1236-1247. ISSN 0012-186X. eISSN 1432-0428. Available under: doi: 10.1007/s00125-020-05117-4
BibTex
@article{Jall2020-06Pharm-51184,
  year={2020},
  doi={10.1007/s00125-020-05117-4},
  title={Pharmacological targeting of α3β4 nicotinic receptors improves peripheral insulin sensitivity in mice with diet-induced obesity},
  number={6},
  volume={63},
  issn={0012-186X},
  journal={Diabetologia},
  pages={1236--1247},
  author={Jall, Sigrid and De Angelis, Meri and Lundsgaard, Anne-Marie and Fritzen, Andreas M. and Nicolaisen, Trine S. and Klein, Anders B. and Stemmer, Kerstin and Clemmensen, Christoffer and Müller, Timo D. and Kleinert, Maximilian}
}
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