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ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity

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Abstract

Purpose

The alpha7 nicotinic acetylcholine receptor (α7nAChR), involved in the modulation of inflammation and insulin sensitivity, is downregulated in white adipose tissue (WAT) of obese patients. This study aims to test the ability of a selective synthetic α7nAChR agonist, the spirocyclic Δ2-isoxazoline derivative (R)-(−)-ICH3 (ICH3), to counteract acute inflammation and obesity-associated modifications in WAT.

Methods

We employed the LPS-septic shock murine model, human primary adipocytes and diet-induced obese (DIO) mice. Inflammatory factor expression was assessed by ELISA and quantitative real-time PCR. Flow cytometry was employed to define WAT inflammatory infiltrate. Insulin signaling was monitored by quantification of AKT phosphorylation.

Results

In the septic shock model, ICH3 revealed antipyretic action and reduced the surge of circulating cytokines. In vitro, ICH3 stimulation (10 µM) preserved viability of human adipocytes, decreased IL-6 mRNA (P < 0.05) and blunted LPS-induced peak of TNFα (P < 0.05) and IL-6 (P < 0.01). Chronic administration of ICH3 to DIO mice was associated with lower numbers of CD8+ T cells (P < 0.05) and to changed WAT expression of inflammatory factors (Hp, P < 0.05; CD301/MGL1, P < 0.01; Arg-1, P < 0.05). As compared to untreated, ICH3 DIO mice exhibited improved insulin signaling in the skeletal muscle (P < 0.01) mirrored by an improved response to glucose load (ipGTT: P < 0.05 at 120 min).

Conclusions

We proved that ICH3 is an anti-inflammatory drug, able to reduce inflammatory cytokines in human adipocytes and to blunt the effects of obesity on WAT inflammatory profile, on glucose tolerance and on tissue insulin sensitivity.

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Acknowledgements

This research has received funding from the European Community's Seventh Framework Programme [FP7/2007–2013] under Grant agreement no. 291778 (DTI-IMPORT).

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Author notes

  1. G. Scabia, R. Cancello and C. Dallanoce have contributed equally to this work.

Authors and Affiliations

  1. CNR Institute of Clinical Physiology, Pisa, Italy

    G. Scabia & M. Maffei

  2. Obesity and Lipodystrophy Center at Endocrinology Unit, University Hospital of Pisa, Pisa, Italy

    G. Scabia, S. Berger, A. Dattilo, I. Barone, G. Ceccarini, F. Santini & M. Maffei

  3. Laboratorio di Ricerche Sull’Obesità, Istituto Auxologico Italiano, IRCCS, Milan, Italy

    R. Cancello & A. Zulian

  4. Department of Pharmaceuticals Sciences, University of Milano, Milan, Italy

    C. Dallanoce, C. Matera & M. De Amici

  5. Dulbecco Telethon Institute, Pisa, Italy

    S. Berger

  6. Life Science Institute, Scuola Superiore Sant’Anna, Pisa, Italy

    A. Dattilo

  7. Laboratorio di Ricerche di Biologia Molecolare, Istituto Auxologico Italiano, IRCCS, Milan, Italy

    A. M. Di Blasio

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Contributions

GS, RC, SB, AD, AZ, IB, and GC performed the experiments in vitro and in vivo; CD and CM synthesized the compound, GS, SB, and FS analyzed the data, GS, RC, SB, MDA, ADB, and MM conceived the experimental design. GS, RC, and MM wrote the paper.

Corresponding authors

Correspondence to A. M. Di Blasio or M. Maffei.

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The authors have nothing to disclose.

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This study was approved by the Ethical Committee of IRCCS-Istituto Auxologico Italiano, and signed informed consent was obtained for adipose tissue sampling during surgery. All animal care protocols and procedures were approved by the Italian Ministry of Health (protocol 108/2015-PR) and all experiments performed in accordance with relevant guidelines and regulations.

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Scabia, G., Cancello, R., Dallanoce, C. et al. ICH3, a selective alpha7 nicotinic acetylcholine receptor agonist, modulates adipocyte inflammation associated with obesity. J Endocrinol Invest 43, 983–993 (2020). https://doi.org/10.1007/s40618-020-01182-z

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