Chronic Exposure to Nicotine Enhances Insulin Sensitivity through α7 Nicotinic Acetylcholine Receptor-STAT3 Pathway

Abstract

This study was to investigate the effect of nicotine on insulin sensitivity and explore the underlying mechanisms. Treatment of Sprague-Dawley rats with nicotine (3 mg/kg/day) for 6 weeks reduced 43% body weight gain and 65% blood insulin level, but had no effect on blood glucose level. Both insulin tolerance test and glucose tolerance test demonstrated that nicotine treatment enhanced insulin sensitivity. Pretreatment of rats with hexamethonium (20 mg/kg/day) to antagonize peripheral nicotinic receptors except for α7 nicotinic acetylcholine receptor (α7-nAChR) had no effect on the insulin sensitizing effect of nicotine. However, the insulin sensitizing effect but not the bodyweight reducing effect of nicotine was abrogated in α7-nAChR knockout mice. Further, chronic treatment with PNU-282987 (0.53 mg/kg/day), a selective α7-nAChR agonist, significantly enhanced insulin sensitivity without apparently modifying bodyweight not only in normal mice but also in AMP-activated kinase-α2 knockout mice, an animal model of insulin resistance with no sign of inflammation. Moreover, PNU-282987 treatment enhanced phosphorylation of signal transducer and activator of transcription 3 (STAT3) in skeletal muscle, adipose tissue and liver in normal mice. PNU-282987 treatment also increased glucose uptake by 25% in C2C12 myotubes and this effect was total abrogated by STAT3 inhibitor, S3I-201. All together, these findings demonstrated that nicotine enhanced insulin sensitivity in animals with or without insulin resistance, at least in part via stimulating α7-nAChR-STAT3 pathway independent of inflammation. Our results contribute not only to the understanding of the pharmacological effects of nicotine, but also to the identifying of new therapeutic targets against insulin resistance.

Nicotinic Cholinergic Signaling in Adipose Tissue and Pancreatic Islets Biology: Revisited Function and Therapeutic Perspectives

“…These benefits are abolished by both the a7-selective antagonist methyllycaconitine and a Janus kinase 2 inhibitor, confirming the involvement of a7 nAChRs and the downstream JAK2/ STAT3 signaling pathway (Marrero et al 2010). Chronic treatment with the selective a7 nAChR agonist PNU-282987 significantly enhances insulin sensitivity in normal mice as well as in insulin-resistant AMP-activated kinasea2 2/2 mice, also in link with enhanced phosphorylation of STAT3 (Xu et al 2012). Together, these preclinical observations in animals suggest that peripheral nicotinic cholinergic signaling could represent a potential therapeutic target for the different forms of diabetes (Table 1).…”

“…In control rats, nicotine administration reduces insulinemia and globally improves insulin sensitivity (Xu et al 2012). In Zucker fatty rats chronically exposed to nicotine, both basal and post-glucose tolerance test glycaemia are reduced (Liu et al 2001).…”

“…a7 nAChR 2/2 mice are gluco-intolerant and resistant to insulin without change in body weight or insulin secretion (Wang et al 2011). Likewise, nicotineinduced insulin-sensitizing action is abrogated in a7 nAChR 2/2 mice (Xu et al 2012). a7 nAChR deficiency seems to elevate adipose tissue infiltration by classically activated macrophages and leads to an inflammatory-prone status which induces insulin resistance.…”

Concomitant alpha7 and beta2 nicotinic AChR subunit deficiency leads to impaired energy homeostasis and increased physical activity in mice

“…Neither sensitivity to glucagon nor neosynthesis of glucose from pyruvate appeared modified in α7β2nAChR −/− mice. Equally, sensitivity to insulin was not changed in α7β2nAChR −/− mice which was more surprising since the single knock-out α7nAChR −/− mouse is gluco-intolerant and resistant to insulin [22,23], due to inflammatoryprone status and increased adipose tissue infiltration by activated macrophages [22]. Unaltered insulin sensitivity in α7β2nAChR −/− mice presently observed is nevertheless consistent with the absence of excessive inflammation in their adipose tissue shown by unchanged TNF-α and IL-6 mRNA levels.…”

“…In contrast, α7nAChR −/− mice present excessive adipose inflammation, impaired glucose tolerance and insulin resistance [22,23].…”