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Gut bacteria in the cecum and large intestine produce SCFAs mainly from nondigestible carbohydrates that pass the small intestine unaffected

plant cell-wall polysaccharides, oligosaccharides, and resistant starches

inulin shifted the relative production of SCFAs from acetate to propionate and butyrate

age of approximately 3–4 years, when it becomes mature

SCFAs affect lipid, glucose, and cholesterol metabolism

colonocytes, the first host cells that take up SCFAs and which depend largely on butyrate for their energy supply

the microbiota educate the immune system and increase the tolerance to microbial immunodeterminants

the microbiota act as a metabolic organ that can break down otherwise indigestible food components, degrade potentially toxic food compounds like oxalate, and synthesize certain vitamins and amino acids

a large part of the SCFAs is used as a source of energy

The general idea is that colonocytes prefer butyrate to acetate and propionate, and oxidize it to ketone bodies and CO2

Exogenous acetate formed by colonic bacterial fermentation enters the blood compartment and is mixed with endogenous acetate released by tissues and organs (103, 104). Up to 70% of the acetate is taken up by the liver (105), where it is not only used as an energy source, but is also used as a substrate for the synthesis of cholesterol and long-chain fatty acids and as a cosubstrate for glutamine and glutamate synthesis

SCFAs regulate the balance between fatty acid synthesis, fatty acid oxidation, and lipolysis in the body.

Fatty acid oxidation is activated by SCFAs, while de novo synthesis and lipolysis are inhibited

obese animals in this study showed a 50% reduction in relative abundance of the Bacteroidetes (i.e., acetate and propionate producers), whereas the Firmicutes (i.e., butyrate producers) were proportionally increased compared with the lean counterparts.

increase in total fecal SCFA concentrations in obese humans.

In humans the distinct relation between the Firmicutes:Bacteroidetes ratio and obesity is less clear.

Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids

a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)

Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase

there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes

To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases

intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers

intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging

dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain

mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment

Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways

unfolded protein response (UPR) machinery

ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases

brain ER stress underlies neurodegenerative diseases

under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival

intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance

prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging

TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense

Most hypothalamic cell types including neurons and glia cells express TLRs

overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs

Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition

hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding

overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain

these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.

circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors

significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components

entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension

Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions

both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.

In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein

IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity

Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition

it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic

this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension

evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition

In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging

intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation

overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved

excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC

oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging

central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations

overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders

chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases

recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations

when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect

autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)

The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases

Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome

Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway

TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase

these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response

TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus

central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.

cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation

central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain

the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance

the hypothalamus, is the central regulator of energy and body weight balance [