Nicotine-mediated upregulation of microRNA-141 expression determines adipokine-intervened insulin resistance
Graphical abstract
Introduction
MicroRNAs (miRNAs) are small non-coding RNAs approximately about 22-nucleotide-long and are thought to be involved in regulating gene expressions of several important enzymes playing pivotal role in metabolic homeostasis (Fu et al., 2013; Joglekar et al., 2011; Poy et al., 2007). miRNAs are transcribed from DNA sequences into primary miRNAs which are latter processed into precursor and mature miRNAs (O’Brien et al., 2018; Peng and Wang, 2018). miRNAs are considered to be involved in various normal physiological functions of the body (Ameres and Zamore, 2013; Fu et al., 2013). Any abnormality in the expression of miRNA may lead to the development of associated diseases (Paul et al., 2018; Tüfekci et al., 2014).
Diabetes mellitus (DM) and insulin resistance (IR) are metabolic disorders with glucolipotoxicity as major clinical manifestation. Several factors notably genetic, environmental, habitual and behavioral may contribute in the development of DM and IR (Piccolo et al., 2016). It has been revealed that among environmental and habitual factors, cigarette smoking is one of the foremost reason for the induction of fatal complications like DM and IR (Rajendran and Uppoor, 2018). Tobacco smoking may provoke inflammation and oxidative stress and can also change mitochondrial-mediated metabolic homeostasis (Luetragoon et al., 2018; Solanki et al., 2018). Cigarette or tobacco contains numerous alkaloids but the active alkaloid is nicotine which contributes for about 95 % of the total alkaloid fraction (Rodgman and Perfetti, 2013). In liver, nicotine is metabolized into metabolites that can bind to protein and DNA of body cell (Taghavi, 2018). One of the major metabolites of nicotine is cotinine which act as biomarker for identification of smokers (Lei et al., 2014; Mattes et al., 2014). Among major physiological effects of nicotine, one is to increase the release of insulin-antagonistic hormones such as catecholamines and cortisol that may lead to the development of IR (Vora and Heise, 2013). Studies have demonstrated that prolonged use of nicotine produces dose-response relationship for IR (Artese et al., 2019; Kelly et al., 2000; Xu et al., 2018). Tobacco promotes the metabolic alteration that may lead toward the risk of metabolic syndrome (Artese et al., 2019; Harris et al., 2016). Moreover, cigarette smoking increases the release of oxygen-free radicals that ultimately decrease the insulin sensitivity (Mouhamed et al., 2016).
Studies have shown that adipocytes are important regulators of glucose and lipid homeostasis. Hence, these are considered as imperative therapeutic targets for the treatment of DM and IR (Fisman and Tenenbaum, 2014; Rehman et al., 2020; Tao et al., 2014). Since long, leptin and adiponectin are well recognized to be most important adipokines released from adipocytes (Rehman et al., 2020; Zhuo et al., 2009). In addition to the production of adipokines, these tissues are also responsible for releasing many cytokines like interleukin-6 (IL-6) which in turn may provoke many health issues like obesity, IR and DM (Jung and Choi, 2014). Glucose homeostasis is controlled and regulated by insulin secretion from β-cells of pancreatic islets. Where the overall function of β-cells of pancreatic islets is regulated by various microRNAs (Feng et al., 2016).
Similarly, a large number of miRNAs are known to be involved in pathogenesis of DM. Glucose metabolism may be influenced and get impaired by dysregulation of microRNAs. miRNA expression profiles of pancreas, adipose tissue, and liver have been shown to alter during pathogenesis of DM and insulin resistance (Guay et al., 2011; Hashimoto and Tanaka, 2017; Zhong et al., 2018). Among various miRNAs, miRNA-141 has been found to be upregulated in different models of tumor, pancreatic cancers and hypoxia and has exhibited positive correlation with increased generation of ROS during these conditions (Chen et al., 2014; Magenta et al., 2011; Xu et al., 2014). It has been well documented that miRNAs are considered to be effective regulators of various pathophysiological pathways of DM and can be among favorable targets for its treatment. Moreover, miRNA-141 has been reported to be positively related with induction of inflammatory responses (Zhang et al., 2015) particularly, IL-6 (Ji et al., 2015). It was also observed to be elevated with increase in lipid peroxidation as indicated by the levels of MDA and liver cell dysfunctioning (Ji et al., 2015). Previous studies have also revealed that cigarette smoking provoke hyperglycemic effects by impairing glucose tolerance and impaired insulin secretion accompanied with increased IR in peripheral tissues (Mouhamed et al., 2016; Xu et al., 2012). Likewise, the expression levels of miR-141 have been reported to relate with smoking history in recent study (Meng et al., 2018). Nevertheless, further aspects of miRNA-141 still needs to be elucidated, hence in view of the above effects of miRNA available in growing literature, the present study was aimed to investigate the level of miRNA-141 in experimental animal model that were exposed with graded doses of nicotine. We further aimed to investigate the possible interplay of this miRNA expression change with adipokine homeostasis and occurrence of insulin resistance in nicotine-exposed experimental animals.
Section snippets
Experimental design
About 30 white albino Wistar male rats weighing around 110−130 g were kept in animal house located in University of Agriculture Faisalabad (UAF), Pakistan. Rats were kept and maintained in a controlled environment with temperature 24 ± 5 °C and 12 h light/ dark cycle with access to water ad libitum. Rats were fed on normal diet and were allowed to acclimatize for two weeks. All experimental procedures were carried out at UAF, in accordance with the approved laboratory animal biosafety
Effect of nicotine exposure on glycemic profile
We exposed experimental rats with different doses of nicotine to observe the effect nicotine exposure on glucose, HbA1c and insulin at different time points i.e. 0 day (before), 15th day (during) and 30th day (end) of treatment period. We observed that blood glucose and serum levels of HbA1c and insulin were not significantly different (P > 0.05) before the administration of different doses of nicotine when compared to control as shown in Fig. 1. However, upon exposure to nicotine, we observed
Discussion
The major constituent of tobacco is nicotine which has shown severe adverse effects on human health. The increased consumption of nicotine in the form of tobacco has become the foremost risk factor to human health worldwide. Tobacco products are still consumed by one third of the world’s population. Nicotine is a tertiary amine alkaloid that contains pyridine and pyrrolidine rings. There are two stereoisomers of nicotine including (S)-nicotine and (R)-nicotine, where (S)-nicotine is considered
Conclusion
Our results demonstrate that expression of miR-141 is greatly inflated upon exposure of nicotine accompanied with elevation of pro-inflammatory cytokines (leptin, IL-6 and IL-β) and lipid peroxidation (upregulation of MDA) by reduction of antioxidant status (G6PDH) and altered adipokines regulation. A strong correlation was found for these parameters with insulin resistance and impaired β-cells functions with increased expression of miRNA-141. This may contribute towards insulin resistance and
CRediT authorship contribution statement
Amna Faheem: Data curation, Formal analysis, Investigation, Writing - original draft. Kanwal Rehman: Conceptualization, Methodology, Validation, Supervision, Project administration, Writing - original draft. Komal Jabeen: Visualization, Writing - review & editing. Muhammad Sajid Hamid Akash: Conceptualization, Methodology, Visualization, Project administration, Writing - review & editing.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgement
This work was financially supported by the research grants (6429/Punjab/NRPU/R&D/HEC/2016 and 8365/Punjab/NRPU/R&D/HEC/2017) received from Higher Education Commission of Pakistan.
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