Several mechanisms are implicated in lipid induced

Several mechanisms are implicated in lipid-induced insulin resistance in muscle, including oxidative stress (Koves et al., 2008, Zhang et al., 2011, Muoio and Neufer, 2012). Mitochondrion is a major source of ROS production. The oxidation of pyruvate and fatty UNC 0646 yielding acetyl-CoA occurs in mitochondria, thus promotes flux through TCA cycle producing NADH and FADH2. The reducing equivalents provide electrons for mitochondrial electron transport chain (ETC) with ROS production due to the leakage of electrons. However, increased FAO, when exceed the ATP demand, will lead to excessive mitochondrial ROS production contributing to insulin resistance (Muoio and Neufer, 2012, Ilkun et al., 2015). Herein, we found that mildronate blunted PA-elicited increased ROS and OCR, and DCA was able to inhibit HFD-induced elevated ROS (H2O2) content in the heart, demonstrating that ROS was at least partially derived from lipid overload-induced disarrangement of substrate oxidation. Excessive mitochondrial ROS also impairs the integrity of mitochondrial membrane, leading to subsequent decrease in Δψm needed for ATP synthesis and permits the entry of ROS into cytoplasma. Complex I in ETC is a main site for ROS production (Mailloux, 2015). Elevated FAO causes an increase in NADH and FADH2 flux into ETC, producing ROS from complex I as well as other sites (Mailloux, 2015, Muoio and Neufer, 2012). Consistently, we observed that PA overload increased complex I activity, in agreement with the report that HFD enhanced the expression of ETC proteins (Turner et al., 2007). This might be adaptive to increased fatty acid supply and β-oxidation but also lead to excessive ROS production impeding insulin signaling partially via serine phosphorylation in IRS-1. In this context, inhibition of mitochondrial oxidative stress by RGSE contributed to restoration of myocardial insulin sensitivity.
Conclusions
Introduction Adipose tissue is the storage site for fatty acids and serves as an energy resource during extreme conditions such as starvation and hibernation. Swift changes in the global food habits as well as growing sedentary life style, is causing an inclination towards incidence of obesity, a chronic multi factorial disease characterised by energy imbalance (Hruby and Hu, 2015). Cardiovascular disorders, hypertension and endocrine disorders are the co morbidities of obesity which impact the life expectancy and quality of life of an individual (Han and Lean, 2016). Nevertheless, the influence of obesity is not only limited to the individual’s physiological status but also influences the socio-economical condition of the subject (Kjellberg et al., 2017). Due to intense biological alterations induced by various risk factors of obesity, the adipose tissue undergoes adaptations such as adipocyte hypertrophy superimposed with hyperplasia (Jo et al., 2009). In addition to these changes, the adipocytes experience a process of cellular differentiation there by converting the pre adipocytes into lipid laden adipocytes resulting in increased fat mass (Tang and Lane, 2012). Moreover, obesity is considered to be the cause as well as consequence of insulin resistance a crucial component of metabolic syndrome. Inevitably these very facts indicate advantage of targeting adipocyte differentiation for management of obesity and its associated metabolic complications (Moseti et al., 2016). Adipogenic differentiation is orchestrated by a complex network of transcriptional factors that regulate the expression of multiple proteins which are crucial for the establishment of differentiated phenotypic adipocyte. The principal transcriptional factors that regulate adipocyte differentiation are the peroxisome proliferator activated receptor gamma (PPAR-γ), CCAT/enhancer binding protein alpha (C/EBPα) and sterol regulatory element binding protein-1c (SREBP-1c) (Fève, 2005, Ji et al., 2015). Amongst these regulators, PPAR-γ is widely expressed in the white adipose tissue and also modulates the lipid metabolism besides controlling adipocyte differentiation. The C/EBP-α is a leucine zipper family transcriptional factor and plays a vital role in induction of terminal differentiation (Rosen et al., 2002, Siersbæk et al., 2010). Finally, SREBP-1c is a major regulator of lipogenic proteins such as fatty acid synthase (FAS) and its activity is under the control of insulin and AMP-activated protein kinase (AMPK) (Moseti et al., 2016). Constitutional activation of PPAR-γ in the absence of other transcription factors can trigger differentiation of immature fibroblasts to mature adipocyte there by establishing its central role in regulation of adipogenic differentiation (Wafer et al., 2017). AMPK is a conserved metabolic sensor of the cell, which is phosphorylated under stress super imposed by low energy states such as higher levels of AMP and ATP ratio. AMPK is activated by phosphorylation at Thr172 along with inhibition of dephosphorylation, this biological sequel leads to shut down of energy consuming anabolic processes and switches on the energy stemming catabolic processes (López and Tena-Sempere, 2017, Daval et al., 2006).