Obesity is a chronic inflammatory state linked to insulin resistance, impaired glucose tolerance and Type 2 diabetes. The cholinergic anti-inflammatory pathway, mediated by nicotinic acetylcholine receptors (nAChRs), represents a novel target in the treatment of obesity and associated complications. We tested the efficacy of a novel spirocyclic Δ2-isoxazoline (R)-(-)-ICH-3 (ICH3), a selective agonist of α7nAChRs, with a five-fold higher binding affinity than PNU-282987, in vitro, on primary human adipose cells from subcutaneous (SAT) and visceral adipose tissue (VAT) and in vivo on mice under LPS-induced inflammation (acute stimulation, 30 mg/Kg) as well as in mice under Diet induced obesity (DIO) (ICH3 chronic stimulation, 20 mg/Kg/day for 4 weeks). In vitro, ICH3 stimulation of SAT and VAT adipocytes resulted in a significant positive modulation of adiponectin gene and down-regulation of interleukin-6 and Tumor Necrosis factor alpha genes (assessed by RTqPCR). In vivo, the acute ICH3 administration resulted in a significant antipyretic effect, while ICH3 chronic administration in DIO mice diminished fasting glucose and affected the leucocytes population infiltrating the epidydimal adipose tissue. These results suggest ICH3 as a safe drug candidate to modulate inflammation and glucose homeostasis in obesity.
Nicotinic anti-inflammatory pathway: a new target to control low-grade inflammation and glucose homeostasis in obesity / R. Cancello, M. Maffei, I. Barone, G. Scabia, Y. Berger, C. Matera, A. Zulian, F. Santini, M. De Amici, C.M.L. Dallanoce, A. Di Blasio. - In: OBESITY FACTS. - ISSN 1662-4025. - 9:suppl. 1(2016 May), pp. 184-184. ((Intervento presentato al convegno European Obesity Summit (EOS) - Joint Congress of EASO and IFSO-EC tenutosi a Gothenburg nel 2016 [10.1159/000446744].
Nicotinic anti-inflammatory pathway: a new target to control low-grade inflammation and glucose homeostasis in obesity
C. Matera;M. De Amici;C.M.L. DallanocePenultimo
;
2016
Abstract
Obesity is a chronic inflammatory state linked to insulin resistance, impaired glucose tolerance and Type 2 diabetes. The cholinergic anti-inflammatory pathway, mediated by nicotinic acetylcholine receptors (nAChRs), represents a novel target in the treatment of obesity and associated complications. We tested the efficacy of a novel spirocyclic Δ2-isoxazoline (R)-(-)-ICH-3 (ICH3), a selective agonist of α7nAChRs, with a five-fold higher binding affinity than PNU-282987, in vitro, on primary human adipose cells from subcutaneous (SAT) and visceral adipose tissue (VAT) and in vivo on mice under LPS-induced inflammation (acute stimulation, 30 mg/Kg) as well as in mice under Diet induced obesity (DIO) (ICH3 chronic stimulation, 20 mg/Kg/day for 4 weeks). In vitro, ICH3 stimulation of SAT and VAT adipocytes resulted in a significant positive modulation of adiponectin gene and down-regulation of interleukin-6 and Tumor Necrosis factor alpha genes (assessed by RTqPCR). In vivo, the acute ICH3 administration resulted in a significant antipyretic effect, while ICH3 chronic administration in DIO mice diminished fasting glucose and affected the leucocytes population infiltrating the epidydimal adipose tissue. These results suggest ICH3 as a safe drug candidate to modulate inflammation and glucose homeostasis in obesity.File | Dimensione | Formato | |
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