Sedentary life style and unhealthy eating habits have resulted in obesity of pandemic proportions worldwide with the number of cases estimated to rise to 1 billion by 2025 as per the World Obesity Federation. Insulin resistance is associated with obesity to different degrees and forms the all-important link between obesity, type 2 diabetes and other diseases comprising the metabolic syndrome. Insulin resistance refers to a state under which there is resistance to the effects of insulin on glucose uptake, its metabolism or storage in three major tissues associated with metabolism-liver, skeletal muscles and adipose tissue.

The mechanisms involved in the development and progression of insulin resistance during obesity are not completely understood but have been found to involve alterations in the glucose and fat metabolism leading to accumulation of fatty acids in the liver and muscles and also abnormal fat accumulation in the adipose tissue [1]. Chronic inflammation and oxidative stress resulting partly due to increased fatty acids (lipotoxicity) are the central pathophysiologic mechanisms driving the development of insulin resistance in the liver, adipose tissue and muscles under obese condition. On one hand, increased circulating fatty acids in the liver cause activation of a number of serine/threonine kinases like ERK, resulting in impairment of the insulin signalling (IRS1/2/AKT/GSK3β pathway) [2,3]. On the other hand, there is activation of the NFkB precipitating in the release of various proinflammatory cytokines like TNFα, IL-6 and IL-1β. Inflammatory cytokines like TNFα suppress the energy sensing kinase-AMPK [4,5] and aggravate insulin resistance via phosphorylating IRS1 at serine and threonine residues [6].

The activity of the master regulator of glucose and lipid homeostasis in the liver, FOXO1 increases under insulin-resistant conditions [7]. Both APMK and AKT can phosphorylate and regulate the activity of FOXO1 [8,9]. We have also reported earlier that under insulin resistance, the epigenetic landscape around the FOXO1 promoter favours its enhanced expression with an increased abundance of H2K36me2 and H3K79me2 and a reduced abundance of H3K27me3 histone marks [10,11]. In addition, the expression of the enzyme EZH2 responsible for establishing the H3K27me3 mark, is reported to be reduced under insulin-resistant conditions [12]. Overall, increased expression of FOXO1 and its increased activation due to reduced activity of AKT and AMPK in insulin resistance results in the over-activation of the gluconeogenic pathway via increased expression of genes like PEPCK and G6Pase increasing hepatic glucose output, further aggravating hyperglycaemia under insulin-resistant conditions [13].

Natural products from plant, animal and microbial sources have been used as therapeutic agents from times immemorial. Most of these products are known to contain secondary metabolites of diverse chemical natures, which possess anticancer, antidiabetic, antioxidant, anti-inflammatory and many other beneficial properties [[14], [15], [16], [17]]. Many molecules of natural origin have also been reported to alter epigenetic processes like DNA methylation, histone modifications and non-coding RNAs [18]. Laccaic acid (LA), chemically a polyhydroxy anthraquinone, is the active constituent of lac dye obtained from the secretion of lac insect Kerria lacca. It is a mixture of structurally similar compounds, Laccaic acid A, B, C, D and E, which are present in a proportion of 40.42%, 17.66%, 2.54%, 1.51% and 20%, respectively [19]. Extensive toxicity studies indicate that it does not produce any significant toxicity after chronic administration, even at a dose of 1000 mg/kg in rats [20,21]. It is approved as a food colouring agent in China (CNS No. 08.104), Japan (Natural additive 394) and Korea (Natural Additive 13). Laccaic acid is known to possess potent antioxidant and anti-inflammatory properties [22,23]. Fagan et al. have reported direct DNMT inhibitory activity of laccaic acid A [24] and Gupta et al. have reported potent anti-tumour activity of laccaic acid in colorectal cancer in Sprague Dawley rats [25] and Kumar et al. have proposed laccaic acid as potential therapeutic modality against cancers of cervix, breast and lungs [26]. The current study was designed to explore the effects of laccaic acid on high-fat diet-induced insulin resistance and to elucidate the molecular mechanisms involved.