In the context of obesity-induced adipose tissue (AT) inflammation, migration of macrophages and their polarization from predominantly anti-inflammatory to proinflammatory subtype is considered a pivotal event in the loss of adipose insulin sensitivity. Two major chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and Fetuin-A (FetA), have been reported to stimulate macrophage migration into inflamed AT instigating inflammation. Moreover, FetA could notably modulate macrophage polarization, yet the mechanism(s) is unknown. The present study was undertaken to elucidate the mechanistic pathway involved in the actions of FetA and MCP-1 in obese AT. We found that FetA knockdown in high fat diet (HFD) fed mice could significantly subdue the augmented MCP-1 expression and reduce adipose tissue macrophage (ATM) content thereby indicating that MCP-1 is being regulated by FetA. Additionally, knockdown of FetA in HFD mice impeded the expression of inducible nitric oxide synthase (iNOS) reverting macrophage activation from mostly proinflammatory to anti-inflammatory state. It was observed that the stimulating effect of FetA on MCP-1 and iNOS was mediated through interferon γ (IFNγ) induced activation of JAK2-STAT1-NOX4 pathway. Furthermore, we detected that the enhanced IFNγ expression was accounted by the stimulatory effect of FetA upon the activities of both cJun and JNK. Taken together, our findings revealed that obesity-induced FetA acts as a master upstream regulator of AT inflammation by regulating MCP-1 and iNOS expression through JNK-cJun-IFNγ-JAK2-STAT1 signaling pathway. This study opened a new horizon in understanding the regulation of ATM content and activation in conditions of obesity-induced insulin resistance.

Obesity, a major global health concern, is characterized by serious imbalance between energy intake and expenditure leading to excess accumulation of fat in adipose tissue (AT). A state of chronic low-grade AT inflammation is prevalent during obesity. The adipose tissue macrophages (ATM) with astounding heterogeneity and complex regulation play a decisive role in mediating obesity-induced insulin resistance. Adipose-derived macrophages were broadly classified as proinflammatory M1 and anti-inflammatory M2 subtypes but recent reports have proclaimed several novel and intermediate profiles which are crucial in understanding the dynamics of macrophage phenotypes during development of obesity. Lipid-laden hypertrophied adipocytes release various chemotactic signals that aggravate macrophage infiltration into AT skewing towards mostly proinflammatory status. The ratio of M1-like to M2-like macrophages is increased substantially resulting in copious secretion of proinflammatory mediators such as TNFα, IL-6, IL-1β, MCP-1, Fetuin-A etc. further worsening insulin resistance. Several AT-derived factors could influence ATM content and activation. Apart from being detrimental, ATM exerts beneficial effects during obesity. Recent studies have highlighted the prime role of AT-resident macrophage sub-populations in not only effective clearance of excess fat and dying adipocytes but also in controlling vascular integrity, adipocyte secretions and fibrosis within obese AT. The role of ATM sub-populations as friend or foe is determined by an intricate interplay of such factors arising within hyperlipidemic microenvironment of obese AT. The present review article highlights some of the key research advances in ATM function and regulation, and appreciates the complex dynamics of ATM in the pathophysiologic scenario of obesity-associated insulin resistance.

The differentiation between chaotic and stochastic systems has long been scrutinized, particularly in observations where data is often noise-contaminated and finite. Our research examines the dual nature of the black hole X-ray binary IGR J17091-3624, an object whose behavior has been closely studied in parallel to GRS 1915+105. Remarkable similarities in the temporal classes of these two objects are explored in literature. However, this was not the case with their non-linear dynamics: GRS 1915+105 shows signs of determinism, while IGR J17091-3624 was found to be stochastic. In this study, we confront the inherent challenge of noise contamination, as in IGR J17091-3624, faced by previous studies, particularly Poisson noise, which adversely impacts the reliability of non-linear results. We employ several denoising techniques to mitigate noise effects and employ methods like Autoencoder, Principal Component Analysis (PCA), Singular Value Decomposition (SVD), and Correlation Integral (CI) to isolate the deterministic signatures. We have found signs of determinism in IGR J17091-3624 after denoising, thus supporting the hypothesis of it being similar to GRS 1915+105, even as a dynamical system.