Nicotine-mediated upregulation of microRNA-141 expression determines adipokine-intervened insulin resistance

Highlights

• Nicotine-mediated adipokine abnormality accelerates progression of metabolic disorders.

• Nicotine exposure promotes inflammatory responses and alter adipokine regulation.

• miRNA-141 indicates adipokine-associated insulin resistance and glucose intolerance.

Abstract

MicroRNAs (miRNAs) are non-coding RNAs that are associated with adipokine homeostasis and insulin resistance. Whereas, smoking can disturb metabolic homeostasis. 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 miRNA-141 expression change with adipokine homeostasis and occurrence of insulin resistance in nicotine-exposed experimental animals. Nicotine (0.5, 1.0, 3.0 and 6.0 mg/Kg) was administered to early adolescent; postnatal days ranging from 25 to 30 Wistar rats for one month. Serum was analyzed for leptin, adipokines, IL-6, MDA, HbA1c, insulin, G6PDH, hexokinase, and lipid profile. While miRNA-141 expression level was determined in plasma. Higher doses of nicotine were associated with higher glucose, HbA1c, leptin, IL-6, MDA and lipids levels, while, insulin, adiponectin, G6PDH, hexokinase and HDL levels were lower. Higher doses of nicotine also impaired glucose tolerance and exhibited significant increase in miR-141 expression signifying that nicotine exposure may influence adipokines regulation altering glycemic profile. This is accompanied with aggravated inflammatory responses where genetic expression of miRNA-141 can be an accessible biomarker for metabolic disturbances with insulin resistance and glucose intolerance.

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.