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Adipocyte and cell biology

Effects of imidazoline-like drugs on liver and adipose tissues, and their role in preventing obesity and associated cardio-metabolic disorders

International Journal of Obesity volume 43, pages 2163–2175 (2019)Cite this article

Subjects

Abstract

Background/Objectives

We previously observed that selective agonists of the sympatho-inhibitory I1 imidazoline receptors (LNP ligands) have favorable effects on several cardiovascular and metabolic disorders defining the metabolic syndrome, including body weight. The objectives of this study were to explore the effects of LNPs on adiposity and the mechanisms involved, and to evaluate their impact on metabolic homeostasis.

Methods

Young Zucker fa/fa rats were treated with LNP599 (10 mg/kg/day) for 12 weeks. Effects on body weight, adiposity (regional re-distribution, morphology, and function of adipose tissues), cardiovascular and metabolic homeostasis, and liver function were evaluated. Direct effects on insulin and AMP-activated protein kinase (AMPK) signaling were studied in human hepatoma HepG2 cells.

Results

LNP599 treatment limited the age-dependent remodeling and inflammation of subcutaneous, epididymal, and visceral adipose tissues, and prevented total fat deposits and the development of obesity. Body-weight stabilization was not related to reduced food intake but rather to enhanced energy expenditure and thermogenesis. Cardiovascular and metabolic parameters were also improved and were significantly correlated with body weight but not with plasma norepinephrine. Insulin and AMPK signaling were enhanced in hepatic tissues of treated animals, whereas blood markers of hepatic disease and pro-inflammatory cytokine levels were reduced. In cultured HepG2 cells, LNP ligands phosphorylated AMPK and the downstream acetyl-CoA carboxylase and prevented oleic acid-induced intracellular lipid accumulation. They also significantly potentiated insulin-mediated AKT activation and this was independent from AMPK.

Conclusions

Selective I1 imidazoline receptor agonists protect against the development of adiposity and obesity, and the associated cardio-metabolic disorders. Activation of I1 receptors in the liver, leading to stimulation of the cellular energy sensor AMPK and insulin sensitization, and in adipose tissues, leading to improvement of morphology and function, are identified as peripheral mechanisms involved in the beneficial actions of these ligands.

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Acknowledgements

This work was financially supported by the SATT Conectus Alsace, the University of Strasbourg, and the Région Alsace (fellowship to MW). We acknowledge Stéphanie Dal and Elodie Seyfritz from the Centre Européen d’Etude du Diabète for their advice and help at imunofluorescence analysis, and Lucie Tischmacher for her technical assistance.

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Author notes

  1. These authors contributed equally: Gaëlle Aubertin and Maud Weiss

Authors and Affiliations

  1. Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire (LPTNC) - EA7296, Faculté de Médecine, Fédération de Médecine Translationnelle, Université de Strasbourg, Strasbourg, France

    Gaëlle Aubertin, Maud Weiss, Florian Traversi, Djamil Benameur, Hugues Greney, Laurent Monassier, Pascal Bousquet & Nathalie Niederhoffer

  2. Imagerie Préclinique - UF6237, Pôle d’imagerie, Hôpitaux Universitaires, Strasbourg, France

    Philippe Choquet

  3. Laboratoire des sciences de l’ingénieur, de l’informatique et de l’imagerie (ICube) - UMR 7357, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France

    Philippe Choquet

  4. Laboratoire de Biochimie et Biologie Moléculaire, Hôpitaux Universitaires, Strasbourg, France

    Nassim Dali-Youcef

  5. Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR7104/INSERM U964/ Université de Strasbourg, Illkirch, France

    Nassim Dali-Youcef

  6. Conception et Application de Molécules Bioactives (CAMB) - UMR7199, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France

    Françoise Pons

  7. Diabète et thérapie cellulaire (DIATHEC) - EA7294, Centre Européen d’Étude du Diabète, Université de Strasbourg, Strasbourg, France

    Séverine Sigrist

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  1. Gaëlle Aubertin
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Aubertin, G., Weiss, M., Traversi, F. et al. Effects of imidazoline-like drugs on liver and adipose tissues, and their role in preventing obesity and associated cardio-metabolic disorders. Int J Obes 43, 2163–2175 (2019). https://doi.org/10.1038/s41366-019-0342-z

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