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Renin catalyses the conversion of AGN to angiotensin I (ATI), which is quickly cleaved by angiotensin converting enzyme (ACE) to form angiotensin II (ATII)

ATII triggers the release of aldosterone from the adrenal glands, which stimulates reabsorption of sodium and water and thereby increases blood volume and blood pressure

ATII also acts on smooth muscle to cause vasoconstriction of the arterioles

ATII promotes the release of antidiuretic hormone from the posterior pituitary gland, which results in water retention and triggers the thirst reflex

ability of non-CSCs to ‘de-differentiate’ into CSCs due to epigenetic or environmental factors, which further increases the complexity of tumour biology and treatment

efficacy of RAS modulators on cancer in both cancer models and cancer patients

A localised (‘paracrine’) RAS mechanism has been identified in many types of cancers, and interruption of the control of the RAS is thought to be the basis for its role in cancer

Components of the RAS are expressed by these CSCs, supporting the hypothesis of the presence of a ‘paracrine RAS’ in regulating these CSCs

Renin is an enzyme normally released by the kidneys in response to falling arterial pressure

a study of GBM demonstrating overexpression of PRR coupled with the observation that inhibition of renin reduces cellular proliferation and promotes apoptosis

PRR has been found to be vital for normal Wnt signalling

A major focus of PRR research is its relationship with Wnt signalling

suggest a crucial role for PRR activation on the proliferation of CSCs, possibly via Wnt/β-catenin signalling, leading to carcinogenesis.

Angiotensin converting enzyme (ACE), also known as CD143, is the endothelial-bound peptidase which physiologically converts ATI to ATII

ACE is crucial in the regulation of blood pressure, angiogenesis and inflammation

results suggest that an overactive ACE promotes cancer growth and progression, and an inhibited or low-activity ACE may have cancer-protective effects

When bound to ATII or ATIII it causes vasoconstriction by stimulating the release of vasopressin, reabsorption of water and sodium by promoting secretion of aldosterone and insulin, fibrosis, cellular growth and migration, pro-inflammation, glucose release from the liver, increased plasma triglyceride concentration, and reduced gluconeogenesis

ATIIR1 is a G-protein-coupled receptor, with downstream signalling involved in vasodilation, hypertrophy and NF-κB activation leading to TNF-α and PAI-1 expression

ATIIR1 has well-documented links with cancer, with one study demonstrating its overexpression in ~20% of breast cancer patients

the effect of RAS dysregulation has been associated with increased VEGF expression and angiogenesis in cancers

In ovarian and cervical cancer, ATIIR1 overexpression has been shown to be an indicator of tumour invasiveness

administration of ATIIR1 blockers (ARBs) have been associated with reduced tumour size, reduction in tumour vascularisation, lower occurrence of metastases, and lower VEGF levels

innate immune system may be causally linked to obesity

adipose tissue contains a substantial population of macrophages, and macrophage-driven adipose inflammation contributes significantly to the pathogenesis of obesity

Collectively, activation of the innate immune system is strongly associated with ASCVD, insulin resistance, and obesity, and recent evidence suggests that much of this association can be traced to a unique family of PRRs known as TLRs

TLRs are a family of type I transmembrane receptors, currently thought to comprise at least 13 members in mammals, that specifically recognize a variety of microbial PAMPs and trigger host cellular responses

Free SFAs have indeed been demonstrated to elicit TLR4-dependent and TLR2-dependent responses in several cell types.

Endogenous SFAs released from adipocytes activate cocultured macrophages via TLR4 [18], indicating the potential for cellular crosstalk in adipose tissue. Collectively, there is a growing body of evidence that SFAs promote, whereas long chain PUFA antagonize, TLR4-dependent and TLR2-dependent signaling in multiple cell models

In an elegant study, Shi et al. [16] demonstrated that SFAs activate TLR4-dependent signaling in both macrophages and adipocytes, and mice lacking TLR4 are protected against insulin resistance driven by intravenous lipid infusion

In addition to effects in macrophages and adipocytes, SFAs can activate TLR4 in the hypothalamus, which triggers a central inflammatory response that results in resistance to anorexigenic signals

endogenous SFAs can indeed promote innate immunity and inflammatory disease

This finding strongly supports the work of Hwang and coworkers [19–22] demonstrating that ω-3 PUFAs can effectively counteract SFA-induced TLR4 activation in cultured macrophages and dendritic cells.

Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells

adipose tissue macrophage (ATM)

Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).

increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).

The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ

well-known regulators of lipid metabolism and mitochondrial activity

Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).

inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)

Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass

JNK, TLR4, ER stress)

NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells

Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity

DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)

saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)

Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)

Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)

Placental inflammation is a characteristic of maternal obesity

a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74

Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB

Nod-like receptor (NLR) family of PRRs

ceramides and sphingolipids

The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.

adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate

Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)

NF-κB, obesity also activates JNK in insulin-responsive tissues

The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors

TLRs are PRRs that recognize microbe-associated molecular patterns

TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain

The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients

Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.

Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption

LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.

In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.

In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.

the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels

dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.

This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.

n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations

it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).

this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A

these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.

This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.

endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis

in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.

T2DM patients have mean values of LPS that are 76% higher than healthy controls

LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic

LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells

Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease

The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile

All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features

LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism

When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome

It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis

On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα

high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs

prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls

Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers

This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation

high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk

LPS has been shown to promote atherosclerosis

markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk

As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.