Nicotinic anti-inflammatory pathway: a new target to control low-grade inflammation and glucose homeostasis in obesity

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.