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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.

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Toll-like receptors (TLRs), a major component of innate immune system, are expressed as membrane or cytosolic receptors on neutrophils, monocytes, macrophages, dendritic cells (DCs), B lymphocytes, Th1, Th2, and regulatory T lymphocytes. It recognizes pathogen-associated molecular patterns (PAMPs) and Toll-interleukin1 (IL-1) receptor (TIR) of various invading pathogens. Downstream signaling of TLRs activates NF-κB, which acts as a transcription factor of pro-inflammatory cytokines, chemokines, and costimulatory molecules. A balance between pro-and anti-inflammatory cytokine protects host body from infectious agents and also induces the healing process. Some of parasitic infections by protozoans and helminths such as Malaria, Leishmaniasis, Trypanosomiasis, Toxoplasmosis, Amoebiasis, Filariasis, Schistosomiasis, Ascariasis, Taeniasis, and Fasciolosis are the leading cause of death and economic loss in both developing and developed nations. Frequent exposure to parasites, immigration, refugee resettlement, increasing immunodeficiency, climate change, drug resistance, lack of vaccination, etc. are the major cause of emerging and re-emerging of the above-stated diseases. However, TLR activation by parasites could stimulate antigen presenting cells and ultimately clear the pathogens by phagocytosis. So, a better understanding of host-parasite interaction in relation to TLR signaling pathway will improve the controlling method of these pathogens in immunotherapy.

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.

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Studies were made in rats bearing the growth hormone secreting tumor (MtTW15). There was (a) a generalized depletion of depot fat with a decrease of its total fatty acidcontent, and increased rate of lipolysis, (b) a rise in the fasting levels of serum FFA detectable only during theearly period of tumor development, and (c) a severe depression of the in vitro metabolism in adipose tissue of glucose to CO2 and fatty acids. The addition of insulin could not restore the lowered values to the basal level of the controls. These findings indicate that chronically elevated levels of GH decrease the glucose utilization and insulin responsivenessof rat adipose tissue and suggest that rats bearing this particular tumor constitute a suitable experimental model for studies on the metabolic effect of hypersommatotropism

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