Imidazoline-like drugs improve insulin sensitivity through peripheral stimulation of adiponectin and AMPK pathways in a rat model of glucose intolerance

Abstract

Altered adiponectin signaling and chronic sympathetic hyperactivity have both been proposed as key factors in the pathogenesis of metabolic syndrome. We recently reported that activation of I1 imidazoline receptors (I1R) improves several symptoms of the metabolic syndrome through sympathoinhibition and increases adiponectin plasma levels in a rat model of metabolic syndrome (Fellmann L, Regnault V, Greney H, et al. J Pharmacol Exp Ther 346: 370-380, 2013). The present study was designed to explore the peripheral component of the beneficial actions of I1R ligands (i.e., sympathoinhibitory independent effects). Aged rats displaying insulin resistance and glucose intolerance were treated with LNP509, a peripherally acting I1R agonist. Glucose tolerance, insulin sensitivity, and adiponectin signaling were assessed at the end of the treatment. Direct actions of the ligand on hepatocyte and adipocyte signaling were also studied. LNP509 reduced the area under the curve of the intravenous glucose tolerance test and enhanced insulin hypoglycemic action and intracellular signaling (Akt phosphorylation), indicating improved glucose tolerance and insulin sensitivity. LNP509 stimulated adiponectin secretion acting at I1R on adipocytes, resulting in increased plasma levels of adiponectin; it also enhanced AMPK phosphorylation in hepatic tissues. Additionally, I1R activation on hepatocytes directly enhanced AMPK phosphorylation. To conclude, I1R ligands can improve insulin sensitivity acting peripherally, independently of sympathoinhibition; stimulation of adiponectin and AMPK pathways at insulin target tissues may account for this effect. This may open a promising new way for the treatment of the metabolic syndrome.

Imidazoline Receptor System: The Past, the Present, and the Future

“…The results of this study showed that the pertussis toxin-sensitive G protein, phosphatidylinositol 3kinase/Akt GSK3b, is coupled with I 1 receptors (Yamanaka et al, 2010). Weiss et al (2015) showed that a ligand selective for I 1 receptors, LNP509, was able to increase the phosphorylation of 59 adenosine monophosphate-activated protein kinase (AMPK) in hepatic cells. AMPK is involved in cellular energy homeostasis.…”

“…Nevertheless, using the binding technique, I 1 imidazoline receptors were shown to be present in the atria and ventricles of rat hearts (El-Ayoubi et al, 2002. Several teams have shown the existence of imidazoline binding sites in adipocytes of different species, including the hamster and rat (MacKinnon et al, 1989;Langin et al, 1990;Fellmann et al, 2013b;Weiss et al, 2015). Weiss et al (2015) demonstrated the existence of specific I 1 binding sites of imidazolines in hepatic cell lines, and Molderings et al (1995) also found fairly abundant amounts in the rat stomach.…”

“…Several teams have shown the existence of imidazoline binding sites in adipocytes of different species, including the hamster and rat (MacKinnon et al, 1989;Langin et al, 1990;Fellmann et al, 2013b;Weiss et al, 2015). Weiss et al (2015) demonstrated the existence of specific I 1 binding sites of imidazolines in hepatic cell lines, and Molderings et al (1995) also found fairly abundant amounts in the rat stomach. In summary, the expression of the specific I 1 binding sites is rather ubiquitous and concerns mainly the CNS but also the digestive and endocrine system, cardiovascular system, and adipose tissue.…”

“…In case of low cellular energy, AMPK increases glucose and fatty acid uptake and oxidation. This activation of the AMPK pathway could explain, at least partially, the favorable effect of I 1 receptor activation on insulin sensitivity (Weiss et al, 2015). In a study of the effects of I 1 receptor activation by moxonidine on the development of hepatic fibrosis, Zhang et al (2017) showed that I 1 receptor activation negatively regulates the course of hepatic fibrosis in an Nrf2-dependent pathway.…”

Imidazoline receptors agonists: possible mechanisms of endothelioprotection

“…2), and the effect on adipocytokines, such as adiponectin as well. (Zuo et al 2015;Weiss et al 2015) 3) Direct effect on endothelial cells:…”