A subsequent study by Yuan et al. showed that Tnf treatment of 3T3L1 adipocytes induces insulin resistance and that this could be prevented by pretreatment of cells with aspirin
Activation of the Tnf receptor results in stimulation of NFκB signaling via Ikkb
the percentage of macrophages in a given adipose tissue depot is positively correlated with adiposity and adipocyte size
Il-10 is an anti-inflammatory cytokine produced by macrophages and lymphocytes
Il-10 exerts its anti-inflammatory activity by inhibiting Tnf-induced NFκB activation by reducing IKK activity [38]
adipose tissue macrophages are responsible for nearly all adipose tissue Tnf expression and a significant portion of Nos2 and Il6 expression
One theory holds that the expansion of adipose tissue leads to adipocyte hypertrophy and hyperplasia and that large adipocytes outstrip the local oxygen supply leading to cell autonomous hypoxia with activation of cellular stress pathways
The use of the anti-inflammatory compounds, salicylate and its derivative aspirin, for treating symptoms of T2DM dates back over 100 years
elevated levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin (IL-8) have all been reported in various diabetic and insulin resistant states
overnutrition and obesity are often accompanied by elevations in tissue and circulating FFA concentrations, and saturated FFAs can directly activate pro-inflammatory responses
Adipokines such as resistin, leptin and adiponectin, which are secreted by adipocytes, can also affect inflammation and insulin sensitivity
In skeletal muscle insulin promotes glucose uptake by stimulating translocation of the GLUT4 glucose transporter
macrophages are also capable of undergoing a phenotypic switch from an M1 state, which was defined as the “classically activated” pro-inflammatory macrophage, to the M2 state or the “alternatively activated” non-inflammatory cell
saturated fatty acids are the most potent inducers of this inflammatory response
Several inducers of insulin resistance, including FFAs, pro-inflammatory cytokines and oxidative stress, activate the expression of Nos2, the gene that encodes iNOS (reviewed in [33]
Adipose tissue insulin signaling results in decreased hormone sensitive lipase activity and this anti-lipolytic effect inhibits free fatty acid (FFA) efflux out of adipocytes.
In the liver, insulin inhibits the expression of key gluconeogenic enzymes and, therefore, insulin resistance in liver leads to elevated hepatic glucose production
elevated JNK activity in liver, adipose tissue and skeletal muscle of obese insulin resistant mice, and knockout of Jnk1 (Jnk1−/−) leads to amelioration of insulin resistance in high fat diet
Adipose tissue from obese mice contains proportionately more M1 macrophages, whereas, lean adipose tissue contains more M2 macrophages, and increased M1 content positively correlates with inflammation, macrophage infiltration and insulin resistance
C-reactive protein (CRP)
these studies highlight the possibility that increased iNOS activity plays a direct role in the pathogenesis of insulin resistance
the important role of Ikkb in the development of obesity and inflammation-induced insulin resistance.
It is probable that local concentrations of inflammatory mediators, such as FFAs, Tnf or other cytokines/adipokines contribute to this polarity switch
Tnf and other cytokines/chemokines are symptomatic of inflammation, and while they propagate and/or maintain the inflammatory state, they are not the initial cause(s) of inflammation
Tlr4, in particular, is stimulated by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria
Tlr4 belongs to the family of Toll-like receptors that function as pattern recognition receptors that guard against microorganismal infections as part of the innate immune system.
Tlr4 stimulation results in the activation of both Ikkb/NFκB and JNK/AP-1 signaling, culminating in the expression and secretion of pro-inflammatory cytokines/chemokines, including, Il1b, IL-6, Tnf, Mcp1, etc. (reviewed in [57
Testosterone has beneficial
effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves
cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart
failure.
testosterone is an L-calcium channel blocker and induces potassium
channel activation in vascular smooth muscle cells
Animal studies have consistently demonstrated that testosterone is atheroprotective,
whereas testosterone deficiency promotes the early stages of atherogenesis
there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes
adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
bidirectional effect between decreased testosterone
concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and
insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular
risk factors
Achieving a normal physiological testosterone concentration through the administration
of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central
adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory
profiles and vascular function
It is well known that impaired erectile function and CVD are closely
related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5
years
no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
free testosterone
levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated
brachial artery vasodilation in men with CAD
Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects
when testosterone is replaced within normal physiological limits in humans
Endothelium-independent mechanisms of testosterone
are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
Testosterone shares the same molecular binding site as nifedipine
Testosterone increases the expression of endothelial nitric oxide synthase (eNOS)
and enhances nitric oxide (NO) production
Testosterone also inhibited
the Ca2+ influx response to PGF2α
one of the major actions of testosterone is on NO and its signalling pathways
In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult
to delineate and may be dependent upon the stage of plaque development
Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate
with serum testosterone
t long-term testosterone treatment reduced CIMT in men with low testosterone levels
and angina
neither intracellular nor membrane-associated
ARs are required for the rapid vasodilator effect
acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described,
primarily in the context of vascular tone regulation via the modulation of gene transcription
Testosterone and DHT increased the expression of eNOS in HUVECs
oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase
inhibition
non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated
human umbilical vein endothelial cells
Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure
in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis
factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM
and/or hypogonadism
patients with the
highest IL1β concentrations had lower endogenous testosterone levels
TRT has been reported to significantly
reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
testosterone treatment to normalise levels in hypogonadal men with the MetS
resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly
men
Higher levels of serum adiponectin have been shown to lower cardiovascular risk
Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ
(IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types
including human endothelial cells
decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in
human endothelial cells when treated with DHT
The key to unravelling the link between testosterone
and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors
and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
testosterone
functions through the AR to modulate adhesion molecule expression
pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
DHT inhibited NFκB activation
DHT could inhibit an LPS-induced upregulation of MCP1
Both NFκB and
AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory
agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis
may reduce or alter any potentially protective effects of testosterone
DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional
level, suggesting that androgens down-regulate IFN-induced genes
(Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT
3β-derivative, 3β-Adiol
TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly
reduced by a pre-incubation with 3β-Adiol in HUVECs
3β-Adiol also reduced LPS-induced gene expression
of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory
effects that are mediated by ER activation.
The authors suggest that DHT differentially
effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and
via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated
an increased risk of adverse cardiovascular events or mortality
The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely
as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase
in either cardiovascular events or mortality in studies up to 12 months
Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse
effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect
or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors,
there may possibly be a cardioprotective action
The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen
and/or disease status.
the majority of studies suggest that testosterone may display both acute and
chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via
endothelium-dependent and -independent mechanisms
The pro-opiomelanocortin (POMC) neurons have an anorexigenic action and, when activated, reduce food intake through the release of two peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine-and-amphetamine-regulated transcripts (CART). The neuropeptide Y (NPY) neurons, on the other hand, release NPY hormone and agouti gene-related protein (AgRP), which prevent the binding of α-MSH to MC3R and MC4R, increasing food intake
This suggests that the central anorexic effects of E2 may occur via ERβ
The main hypothalamic areas involved in food intake and satiety are the arcuate nucleus (ARC), the lateral hypothalamus (LH), the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), and the dorsomedial hypothalamus (DMH)
Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure
E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution
ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake
It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.
Both ERs have been identified in the ARC
Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.
Both ERs have been identified in the LH
both ERs have been identified in this nucleus
The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive
The VMH is ERα regulated
Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body
GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake
data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance
In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane
It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.
E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue
In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue
decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin
Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance
Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs
Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue
suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue
very nice article that looks at the balance of ER-alpha/ER-beta and their role in metabolic syndrome. This article discusses the balance of these receptors are tissue dependent in their effect. I like their conclusion: "...but these mechanisms will never be completely understood if they are not considered in the context of a whole system.
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
PPARs play pivotal in obesity. PPARs appear to reduce the inflammatory cascade associated with obesity. Downregulation of PPARs are associated with increased inflammation. Natural PPARs include unsaturated fats and eicosanoids.
Mechanistic studies further showed that such metabolic inflammation is related to the induction of various intracellular stresses such as mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and autophagy defect under prolonged nutritional excess
intracellular stress-inflammation process for metabolic syndrome has been established in the central nervous system (CNS) and particularly in the hypothalamus
the CNS and the comprised hypothalamus are known to govern various metabolic activities of the body including appetite control, energy expenditure, carbohydrate and lipid metabolism, and blood pressure homeostasis
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 [