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secretion of MCP-1, resistin, and other proinflammatory cytokines is increased by obesity, the adipose secretion of the anti-inflammatory protein adiponectin is decreased

the peroxisome proliferators- activated receptor (PPAR) family are involved in the regulation of inflammation and energy homestasis

natural agonists, including unsaturated fatty acids and eicosanoids

PPARα also regulates inflammatory processes, mainly by inhibiting inflammatory gene expression

upregulation of COX-2 is seen in alcoholic steatohepatitis and nonalcoholic steatohepatitis and has been directly linked to the progression of steatosis to steatohepatitis, the inhibitory effect of PPARα on COX-2 may reduce steatohepatitis

PPARα agonists have a clear anorexic effect resulting in decreased food intake, evidence is accumulating that PPARα may also directly influence adipose tissue function, including its inflammatory status.

PPARα may govern adipose tissue inflammation in three different ways: (1) by decreasing adipocyte hypertrophy, which is known to be connected with a higher inflammatory status of the tissue [3, 11, 59], (2) by direct regulation of inflammatory gene expression via locally expressed PPARα, or (3) by systemic events likely originating from liver

PPARγ is considered the master regulator of adipogenesis

Unsaturated fatty acids and several eicosanoids serve as endogenous agonists of PPARγ

PPARγ2, which is adipose-tissue specific

two different molecular mechanisms have been proposed by which anti-inflammatory actions of PPARγ are effectuated: (1) via interference with proinflammatory transcription factors including STAT, NF-κB, and AP-1

and (2) by preventing removal of corepressor complexes from gene promoter regions resulting in suppression of inflammatory gene transcription

diet-induced obesity is associated with increased inflammatory gene expression in adipose tissue via adipocyte hypertrophy and macrophage infiltration

PPARγ is able to reverse macrophage infiltration, and subsequently reduces inflammatory gene expression

Inflammatory adipokines mainly originate from macrophages which are part of the stromal vascular fraction of adipose tissue [18, 19], and accordingly, the downregulation of inflammatory adipokines in WAT by PPARγ probably occurs via effects on macrophages

By interfering with NF-κB signaling pathways, PPARγ is known to decrease inflammation in activated macrophages

Recent data suggest that activation of PPARγ in fatty liver may protect against inflammation

PPARs may influence the inflammatory response either by direct transcriptional downregulation of proinflammatory genes

anti-inflammatory properties of PPARs in human obesity

Thus, while glucose metabolism is negatively regulated by phosphofructokinase, fructose can continuously enter the glycolytic pathway. Therefore, fructose can uncontrollably produce glucose, glycogen, lactate, and pyruvate, providing both the glycerol and acyl portions of acyl-glycerol molecules. These particular substrates, and the resultant excess energy flux due to unregulated fructose metabolism, will promote the over-production of TG (reviewed in [53]).

Glycemic excursions and insulin responses were reduced by 66% and 65%, respectively, in the fructose-consuming subjects

reduction in circulating leptin both in the short and long-term as well as a 30% reduction in ghrelin (an orexigenic gastroenteric hormone) in the fructose group compared to the glucose group.

A prolonged elevation of TG was also seen in the high fructose subjects

Both fat and fructose consumption usually results in low leptin concentrations which, in turn, leads to overeating in populations consuming energy from these particular macronutrients

Chronic fructose consumption reduces adiponectin responses, contributing to insulin resistance

A definite relationship has also been found between metabolic syndrome and hyperhomocysteinemia

the liver takes up dietary fructose rapidly where it can be converted to glycerol-3-phosphate. This substrate favours esterification of unbound FFA to form the TG

Fructose stimulates TG production, but impairs removal, creating the known dyslipidemic profile

the effects of fructose in promoting TG synthesis are independent of insulinemia

Although fructose does not appear to acutely increase insulin levels, chronic exposure seems to indirectly cause hyperinsulinemia and obesity through other mechanisms. One proposed mechanism involves GLUT5

If FFA are not removed from tissues, as occurs in fructose fed insulin resistant models, there is an increased energy and FFA flux that leads to the increased secretion of TG

In these scenarios, where there is excess hepatic fatty acid uptake, synthesis and secretion, 'input' of fats in the liver exceed 'outputs', and hepatic steatosis occurs

Carbohydrate induced hypertriglycerolemia results from a combination of both TG overproduction, and inadequate TG clearance

fructose-induced metabolic dyslipidemia is usually accompanied by whole body insulin resistance [100] and reduced hepatic insulin sensitivity

Excess VLDL secretion has been shown to deliver increased fatty acids and TG to muscle and other tissues, further inducing insulin resistance

the metabolic effects of fructose occur through rapid utilization in the liver due to the bypassing of the regulatory phosphofructokinase step in glycolysis. This in turn causes activation of pyruvate dehydrogenase, and subsequent modifications favoring esterification of fatty acids, again leading to increased VLDL secretion

High fructose diets can have a hypertriglyceridemic and pro-oxidant effect

Oxidative stress has often been implicated in the pathology of insulin resistance induced by fructose feeding

Administration of alpha-lipoic acid (LA) has been shown to prevent these changes, and improve insulin sensitivity

LA treatment also prevents several deleterious effects of fructose feeding: the increases in cholesterol, TG, activity of lipogenic enzymes, and VLDL secretion

Fructose has also been implicated in reducing PPARα levels

PPARα is a ligand activated nuclear hormone receptor that is responsible for inducing mitochondrial and peroxisomal β-oxidation

decreased PPARα expression can result in reduced oxidation, leading to cellular lipid accumulation

fructose diets altered the structure and function of VLDL particles causing and increase in the TG: protein ratio

LDL particle size has been found to be inversely related to TG concentration

therefore the higher TG results in a smaller, denser, more atherogenic LDL particle, which contributes to the morbidity of the metabolic disorders associated with insulin resistance

High fructose, which stimulates VLDL secretion, may initiate the cycle that results in metabolic syndrome long before type 2 diabetes and obesity develop

A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, disturbs normal hepatic carbohydrate metabolism leading to two major consequences (Figure 2): perturbations in glucose metabolism and glucose uptake pathways, and a significantly enhanced rate of de novo lipogenesis and TG synthesis, driven by the high flux of glycerol and acyl portions of TG molecules coming from fructose catabolism

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.