Download Crosstalk Between Insulin and Toll-like Receptor

Mol Neurobiol
DOI 10.1007/s12035-013-8631-3
Crosstalk Between Insulin and Toll-like Receptor Signaling
Pathways in the Central Nervous system
Fatemeh Hemmati & Rasoul Ghasemi & Norlinah Mohamed Ibrahim &
Leila Dargahi & Zahurin Mohamed & Azman Ali Raymond &
Abolhassan Ahmadiani
Received: 11 December 2013 / Accepted: 25 December 2013
# Springer Science+Business Media New York 2014
Abstract Neuroinflammation is known as a key player in a
variety of neurodegenerative and/or neurological diseases. Brain
Toll-like receptors (TLRs) are leading elements in the initiation
and progression of neuroinflammation and the development of
different neuronal diseases. Furthermore, TLR activation is one
of the most important elements in the induction of insulin
resistance in different organs such as the central nervous system.
Involvement of insulin signaling dysregulation and insulin resistance are also shown to contribute to the pathology of neurological diseases. Considering the important roles of TLRs in
neuroinflammation and central insulin resistance and the effects
of these processes in the initiation and progression of neurodegenerative and neurological diseases, here we are going to
review current knowledge about the potential crosstalk between
TLRs and insulin signaling pathways in neuroinflammatory
disorders of the central nervous system.
Fatemeh Hemmati and Rasoul Ghasemi contributed equally to this work
and should be considered as co-first authors.
F. Hemmati : N. Mohamed Ibrahim : A. A. Raymond
Department of Medicine, Universiti Kebangsaan Malaysia Medical
Centre, Cheras, Kuala Lumpur, Malaysia
R. Ghasemi
Neuroscience Research Center and Department of Physiology,
Shiraz University of Medical Sciences, Shiraz, Iran
L. Dargahi : A. Ahmadiani
NeuroBiology Research Center, Shahid Beheshti University
of Medical Sciences, Tehran, Iran
L. Dargahi : A. Ahmadiani
Neuroscience Research Center, Shahid Beheshti University
of Medical Sciences, Tehran, Iran
Z. Mohamed : A. Ahmadiani (*)
Department of Pharmacology, Faculty of Medicine,
University of Malaya, 50603 Kuala Lumpur, Malaysia
e-mail: [email protected]
Keywords Insulin . Toll-like receptors .
Neuroinflammation
Introduction
For several decades, the brain is considered as an immuneprivileged organ which is not affected by the immune system.
It is now clear that the central nervous system (CNS) not only
has its own immune response mechanisms, but also under
appropriate conditions, inflammatory cells and factors could
cross the blood-brain barrier (BBB) to access the CNS [1].
However, inflammatory responses in the CNS serve to protect
the brain tissue against insulting stimuli, but it could turn into
a destructive process [2], to the extent that neuroinflammation
is known as a key player in several neurological diseases such
as Alzheimer’s disease (AD), Parkinson’s disease (PD) as well
as psychiatric disorders [3–6]. Toll-like receptors (TLRs) are
among the most important contributors in the initiation and
progression of neuroinflammatory processes. TLRs are a
group of glycoproteins that are widely expressed within the
CNS and recognize pattern-associated molecular patterns
(PAMPs) as well as endogenous danger signals (damageassociated molecular patterns or DAMPs). TLRs play an
essential role in the mediation of immune responses and
CNS repair and development, and along with these roles,
TLRs play a central role in the pathology of different neurological disorders [7, 8]. TLRs are also shown to contribute to
the impairment of insulin signaling in different organs including
the CNS [9, 10]. Given that insulin signaling plays a central role
in the physiological functions of the CNS (reviewed in [11])
and disruption of insulin signaling is a key contributor in the
pathology of neurological diseases (reviewed in [12]), hereby
we review the latest documents about TLRs and their roles in
the physiology and pathology of the CNS, considering its
possible interaction with insulin signaling pathway.
Mol Neurobiol
Neuroinflammation
Inflammation is defined as a highly regulated biological response to harmful stimuli such as infectious agents and tissue
injury which is brought about by activation of resident as well
as recruitment of migrating inflammatory cells. Primarily,
inflammatory responses play a protective role against invading pathogens; however, it also contributes to the pathology of
many chronic diseases [13]. Inflammatory responses are classified into two types—acute and chronic. Whereas acute inflammation is mostly beneficial and allows the inflamed organ
to limit the proliferation of invading pathogens and facilitate
their clearance, more persistent chronic inflammation could
result in pathogenic processes [14].
The presence of tight BBB and the resulting limited entrance of immune cytokines, in addition to a low level of
MHC and adhesion molecules and lower rejection of transplants within the CNS, all raised a notion that the CNS is an
immune-privileged organ which is not susceptible to inflammation or immune activation. This old concept now has been
revolutionized by accumulating evidences showing that the
CNS has its own immune susceptibility and it can be affected
by immune responses [1, 15]. It is well documented that
disruption of BBB and the resulting entrance of immunological mediators accompanied by production and release of these
mediators via CNS cells (particularly microglial cells) initiate
a more restrictive type of inflammation named as neuroinflammation [1, 16]. Neuroinflammatory responses are shown
to be somehow different from the inflammatory response
elsewhere. For instance, edema as a typical phenotype of
inflammation is limited in the CNS (because of the cranium).
Another difference which can be seen in neuroinflammation is
the recruitment of leucocytes, which is very rapid in systemic
organs, but in the CNS, it is delayed. In spite of this delayed
recruitment of leucocytes in the brain, microglial activation
and release of inflammatory mediators are shown to be rapid
(reviewed in [1]).
Mechanisms: Cells, Receptors, and Mediators
Several types of cells within the CNS are shown to be involved in the initiation and regulation of immune responses.
These cells are categorized into two groups: (1) residential
cells such as microglia, astrocytes, and endothelial cells and
(2) infiltrating cells such as T cells and macrophages [15].
Similar to inflammatory responses in extraneuronal organs,
neuroinflammatory responses are also elicited by both exogenous and endogenous stimuli, and recognition of these stimuli and triggering of inflammatory responses in the CNS is
carried out through different classes of receptors.
Pattern Recognition Receptors (PRRs) These are activated by
pathogen-associated molecular patterns (PAMPs) derived
from exogenous stimuli (such as lipopolysaccharide (LPS), viral
double-stranded RNA) and endogenously derived molecules
(such as components of necrotic cells and molecules formed
by pathogenic mechanisms). TLRs are one class of this receptor family. These receptors are expressed widely in CNS cells
and play a role in the physiology and pathophysiology of the
CNS (TLRs will be described in the succeeding sections) [17].
Purinergic Receptors These receptors are expressed on microglia and astrocytes and are activated by ATP released from
injured and/or dead cells [18].
Scavenger Receptors Different cell types in the CNS including microglia and astrocytes express these receptors, and they
participate in the uptake of both native and pathologically
modified substances and play a role in host defense against
bacterial pathogens [19].
Under physiological conditions, microglial cells “as the
main cellular component of CNS immune response” are in
inactive form, and upon detection of danger signals (either
pathogen invasion or tissue damage), these cells switch to
their active immunological form which releases inflammatory
mediators (e.g., IL-1β, TNF-α). Secretion of these cytokines
from microglia ultimately leads to activation of astrocytes and
secondary inflammatory response will be ignited in the CNS
[20, 21]. If the acute inflammatory response fails to resolve the
stimulus and/or the inflammatory stimuli persists for a longer
time, feed-forward loops would be started and its resulting
uncontrolled neuroinflammatory response would leave detrimental effect on the CNS, a process which could be seen in
many neurodegenerative and neurological diseases [20].
Toll-like Receptors
Toll-like receptors (TLRs) are a family of type I transmembrane glycoproteins which play an essential role in the immune system. Structurally, TLRs are characterized by a number of leucine-rich repeats (LRR) in the extracellular domain
which participate in the ligand recognition, followed by a
LRR carboxy-terminal domain which separates LRR from
the transmembrane domain and a conserved intracellular
Toll/IL-1 receptor (TIR) domain [22].
The primary function of TLRs as PRRs is the detection of
specific molecular patterns named as PAMPs. PAMPs sensed
by TLRs are structural components (such as lipids, proteins,
lipoproteins, and nucleic acids) derived from bacteria, viruses,
fungi, and parasites [23, 24]. TLRs also take part in the
recognition of endogenous ligands mainly derived from tissue
damage and cellular stress, and these ligands are known as
danger (damage)-associated molecular patterns (DAMPs). By
this way, TLRs participate in sterile inflammatory responses
observed in various pathological processes [25].
Mol Neurobiol
To date, 10 and 13 members of TLRs have been identified in
human and mouse. The majority of these members (TLR1–9)
are conserved in both species, and TLR11, 12, and 13 are only
present in the mouse genome, while TLR10 seems to be an
inactive form [24].
Based on their subcellular localization, TLRs are categorized into two groups: a group consisting of TLR1, 2, 4, 5, 6,
and 11 which are expressed on the cell surface and mainly
senses membrane-derived structures such as lipids, lipoproteins, and proteins. Another group including TLR3, 7, 8, and 9
is present in the intracellular compartments such as the endoplasmic reticulum (ER), endosomes, and endolysosomes and
recognizes bacterial or virus nucleic acids. This subcellular
localization is mainly determined by transmembrane and
membrane-proximal regions of TLRs [26].
It has been shown that recognition of different ligands is
carried out via different members of the TLR family. While
TLR2/TLR1 dimer senses bacterial triacylated lipopeptides,
the TLR2/TLR6 dimer is responsible for the recognition of
diacylated lipopeptides. In such a way, TLR3 detects doublestranded RNA (dsRNA), TLR4 is mainly specific for LPS and
host-derived ligands such as HSPs and fibronectin, TLR5
senses bacterial flagellin, TLR7 and TLR 8 act as sensor for
single-stranded RNAs (ssRNA), and finally, nonmethylated
cytosine guanosine (CPG) DNAs are recognized by TLR9.
Host-derived ligands such as HSPs and fibronectin, saturated
fatty acids, oligosaccharides of hyaluronic acid, and polysaccharide fragments of heparin sulfate are mainly detected by
TLR4 and TLR2 [26–29].
associated kinase (IRAK1 and 4) and phosphorylation of both
IRAK1 and 4. IRAK1 and IRAK4 phosphorylation then causes
an active oligomer between IRAKs and tumor necrosis factor
receptor-associated factor-6 (TRAF-6) to be formed. TRAF-6 in
turn activates transforming growth factor-β-activated protein
kinase 1 (TAK1), and in the next step, TAK1 forms a complex
with TAK1-binding protein (TAB1, 2, and 3) and activates Ik B
kinase (IKK). Activated IKK would be able to induce phosphorylation of Ik B, tagging it for degradation. Once Ik B is
degraded, NF-ĸB is freed to enter the nucleus and initiates the
transcription of various inflammatory genes. Concurrent with
the activation of IKK, TAK1 also phosphorylates two members
of the MAP kinase kinase family (MKK3 and MKK6), and by
this pathway, P38 and JNK mitogen-activated protein kinases
(MAPKs) are activated by TLRs. Subsequently, P38 and JNK
translocate to the nucleus and initiate the transcription of activator protein-1 (AP1) and c-Jun target genes (Fig. 1). TLRs also
activate the third member of the MAPK family (ERK) through
MEK1 and MEK2, but the exact pathway linking TLRs to
MEK/ERK activation remains to be elucidated (reviewed in
[29, 32]). MyD88-independent pathway is carried out via another adaptor protein, TRIF. In this pathway, TRIF binds simultaneously to TRAF-6 and receptor interacting protein (RIP) and
this ultimately leads to NF-ĸB and JNK activation. TRIF binding to TLR3 also initiates another MyD88-independent pathway
which is carried out via recruitment of TRAF3 and subsequent
activation of TRAF-associated NF-ĸB activator (TANK)
binding kinase (TBK1), and this kinase then phosphorylates
interferon regulatory factors (IRF), finally leading to interferon release. In this way, cells try to fight against the virus
that activated TLR3 (reviewed in [32]) (Fig. 2).
TLR Signaling Pathway
TLR Interaction with Insulin Signaling Pathway
When TLRs bind to their ligands, the first step in the initiation of
intracellular signaling pathways is recruitment of TIRcontaining adaptor proteins, and these adaptor proteins then
regulate which intracellular pathway will be activated [27].
Generally, five adaptor proteins have been identified that interact
with the TIR domain of TLRs and play a role in the initiation
and progression of the TLR signaling pathway. These adaptor
proteins are myeloid differentiation factor-88 (MyD88), MyD88
adaptor-like protein (Mal), TIR domain-containing adaptor protein inducing IFNβ (TRIF), TRIF-related adaptor molecule
(TRAM), and sterile α- and armadillo-motif-containing protein
(SARM) [29, 30]. Based on the adaptor protein used by TLRs,
intracellular signaling of TLRs is divided into two pathways:
MyD88-dependent signaling pathway which is used by majority
of TLRs (except TLR3) and MyD88-independent signaling
pathway which is used by TLR3 and TLR4. It is evident that
TLR4 is the only TLR that can rely on both pathways [31]. In
MyD88-dependent pathway, binding of MyD88 to the receptor
is followed by an association between MyD88 and IL receptor-
Initial evidence for the association between insulin resistance
and inflammation dates back to more than 100 years ago [33].
Several decades later, it was shown that while administration of
proinflammatory cytokine (TNF) to diabetic rats exacerbated
their hyperglycemia [34], genetic deletion as well as neutralizing TNF-α was associated with improved insulin sensitivity
[35, 36]. These clearly indicated that inflammatory pathways
are major contributors in the induction of insulin resistance.
Since TLRs play an essential role in the inflammatory pathways, then it would be conceivable to assume that TLRs may
participate in the induction of insulin resistance; to date, large
numbers of evidences supporting this view have been published
[37–40]). As mentioned, TLRs are shown to be expressed in the
CNS; therein, they are involved in the physiology and pathophysiology of the CNS. Studies have shown that like peripheral
tissues, TLRs (particularly TLR2 and 4) have an important role
in the induction of central insulin resistance. It has been shown
that central insulin resistance induced by high fat diet (HFD) or
obesity and its resulting reduction in neuronal activity and
TLR Members
Mol Neurobiol
Fig. 1 Illustration of the different
ligands activating TLRs and their
resulting MyD88-dependent
pathway of TLR signaling. IKK Ik
B kinase, IRAK IL receptorassociated kinase, IRF interferon
regulatory factors, MAL MyD88
adaptor-like protein, SARM sterile
α- and armadillo-motifcontaining protein, TAB TAK1binding protein, TRAF-6 tumor
necrosis factor receptorassociated factor-6, TANK TRAFassociated NF-ĸB activator, TBK1
TANK binding kinase, TAK1
transforming growth factor-βactivated protein kinase 1, TRIF
TIR domain-containing adaptor
protein inducing IFNβ, TRAM
TRIF-related adaptor molecule
locomotion could be prevented by genetic deletion of TLR2/4,
or neutralizing inflammatory mediators suggesting that TLRinduced neuroinflammatory responses is a causative factor in
the induction of central insulin resistance [41, 42]. Consistently,
the association between reduction in brain insulin sensitivity
and TLR-induced elevation of inflammatory cytokines has also
been reported [43, 44]. In addition, genetic deletion of TLR2/4
in mice causes astrocytic insulin actions and markers of glycogen synthesis to be increased, showing that besides neurons,
TLRs also affect insulin responsiveness in the astrocytes [42].
Considering these evidences showing that TLRs are main contributors in the induction of brain insulin resistance and the
magnificent roles which insulin dysregulation and TLR signaling pathway play in the pathology of different neurological
diseases, in the next sections, we will address the current
literature about the presence and roles of TLRs in the CNS,
and then the possible interactions between insulin and TLR
signaling pathways in the initiation and progression of some
major pathologies of the CNS will be reviewed.
TLRs in the Brain
Expression
Accumulating evidences are available indicating that TLRs
are expressed in different cellular compartments of the CNS.
In humans, it has been shown that microglia and astrocytes
express all functional TLRs (TLR1–9), but other cells express
just a number of them. For instance, oligodendrocytes
express TLR2 and 3; endothelial cells express TLR2, 4,
and 9; and finally, neuronal cells are shown to express
TLR2, 3, 4, 8, and 9 [45, 46]. It is noticeable that TLR
expression is not constant, and in response to different
stimuli like pathogens, cytokines, and environmental stresses,
their expression is modulated [28].
TLR Functions in the CNS
Besides the important roles of TLRs in the modulation of
immune responses within the CNS, these receptors also possess several other functions in the physiology of the CNS. One
of these important roles of TLRs is their developmental roles
during embryogenesis. It has been shown that neural progenitor cells (NPCs) express TLR2, 3 and 4, and these receptors
are implicated in the proliferation as well as differentiation of
NPCs. Furthermore, several aspects of adult neuronal physiology such as neurogenesis, neural survival, structural plasticity, and neurite outgrowth are also shown to be modulated
by TLRs. As these processes are the main features of the
cognitive function of the CNS, it would be conceivable to
conclude that TLRs are implicated in cognition and memory.
Consistently, several lines of evidences are published showing
that members of TLRs contribute in the modulation of
Mol Neurobiol
Fig. 2 Illustration of the different
ligands activating TLR3 and
TLR4 and their resulting
MyD88-independent pathway
of TLR signaling. See Fig. 1
for abbreviations
TLR4
activation
LPS, HSPs,hyalurnic
acid , viral proteins...
dsRNA
TLR
activation
TRAM
TRAF-3
TBK1
TRIF
RIP1
TRAF-6
TAB1,2,3
IKK
activation
IRF-3
phosphorylation
Type I IFN
p-IRF3
TAK1
I kB
degradation
MAPKs
phosphorylation
NF-kB
AP1/C-JUN
NF-kB
AP1
C-Jun
Inflammatory cytokines
Nucleus
different types of memory (reviewed in [47]). In addition to
the aforementioned physiological functions, TLRs are also
involved in the pathogenesis of different neurodegenerative
and neurological diseases [47].
interacting signaling pathways which possibly contribute in
these pathologies will be discussed in more detail.
Participation of TLRs and Insulin Dysregulation in Brain
Pathologies
AD is one the most prevalent neurodegenerative disorders
which TLRs and insulin impairment play a role in its pathophysiology. AD is characterized by intercellular neurofibrillary tangles (NFT) and extracellular senile plaques composed
of an aggregated form of amyloid beta (Aβ) peptides. These
plaques are surrounded by activated microglia and monocytic
phagocytes of the brain, and Aβ peptides act as the main
stimulator of microglia activation, thereby senile plaques are
known as the main foci of local inflammatory responses in AD
brains [48]. A number of TLR family members play a pivotal
role in Aβ-induced microglia activation, as it has been shown
that in microglial cells lacking TLR2 and TLR4, amyloid beta
fails to activate P38 and induce cytokine production. In addition, deletion of TLRs in mouse models of AD causes the
level of P38 and NF-ĸB to be lower than that of normal AD
models [49, 50]. It must be emphasized that activation of
As mentioned, TLRs and impairment of insulin signaling are
commonly involved in some important pathological states of
the CNS. On the other side, we pointed to literatures which
show a positive correlation between TLR activation and
development of insulin resistance, and these evidences
raise a possibility that adverse effects of neuroinflammation and TLR overactivity in neurodegenerative diseases
like AD may be carried out, at least partly, through their
deteriorating effects on insulin signaling. In the coming
sections, shared involvement of TLRs and insulin dysregulation in the pathology of neurodegenerative diseases like
AD and PD as well as neuropsychiatric disorders will be
briefly reviewed, and the in the next section, the common
Alzheimer’s Disease
Mol Neurobiol
TLRs by Aβ is not always a harmful pathway, in fact, in early
stages of AD, when the Aβ concentration is low, activation of
TLRs promotes Aβ clearance by activating microglial uptake
[51]. Consistently, it has been demonstrated that Aβ accumulation and memory impairment are increased in mice lacking
TLR2 [52]. When the concentration of amyloid beta is high, a
situation which can be seen in later stages of AD, TLR
activation not only causes detrimental neuroinflammatory
pathways to be activated but also microglial mediated phagocytosis of Aβ is inhibited by released cytokines [53–55].
Besides the participation of TLRs in AD, substantive evidences
also have been published showing that dysregulation of insulin
signaling is associated with the development of AD, and
impairment of insulin signaling is known as a key pathological hallmark of AD. This clear involvement of insulin
disturbance in AD is so much that AD is alternatively
named as “diabetes type 3” (reviewed in [12]).
Parkinson’s Disease
Parkinson’s disease is another prevalent neurodegenerative
disease which TLR activity and insulin dysregulation are
commonly involved in its pathophysiology. PD is caused by
a progressive loss of dopaminergic neurons of the substantial
nigra pars compacta (SNpc) [56]. Release of various proinflammatory cytokines such as IL-1β, TNF-α, interferon-γ,
and NO by activated microglial cells of SNpc and its resulting
neuroinflammation is believed to play an important role in the
neurodegenerative process of this disease [57]. TLRs are the
main mediators for triggering of this microglial activation.
Accordingly, it has been demonstrated that MPTP administration to TLR4-deficient mice causes less microglial activation
when compared with wild-type ones [58]. Furthermore, upregulation of TLRs (TLR3, 4, 7, 9) as well as the key adaptor
of TLR signaling (MyD88) was also shown in MPTP-treated
mice and postmortem parkinsonian brains [59, 60]. These
studies and others clearly indicate that some members of the
TLR family are directly involved in the pathology of PD. On
the other hand, considerable evidences are available showing
that the substantial nigra expresses insulin receptors where
insulin protects dopaminergic neurons and plays a role in the
regulation of dopamine synthesis, in such a way that insulin
disturbances are shown to be associated with the development
and progression of PD (reviewed in [12]).
Psychiatric Disorders
In addition to neurodegenerative diseases, insulin impairment
and TLR-brought neuroinflammation are also commonly involved in the pathology of psychiatric disorders. Consistently,
it has been shown that injection of inflammatory cytokines
(IL-1β, TNF-α) to healthy animals induces behavioral deficits
and social withdrawal named as sickness behavior [4].
Meanwhile, involvement of prenatal TLR3 activation in the
development of behavioral deficits in adult offspring is also
documented [61, 62]. In agreement with these evidences, it
was depicted that in blood samples obtained from schizophrenia and bipolar patients, TLR agonists induce higher levels of
IL-1β, IL-6, IL-8, and TNF-α release when compared with
bloods of healthy people. This observation shows that these
disorders are associated with an altered TLR-mediated immune response [63]. Concomitantly, involvement of insulin
signaling dysregulation in the pathology of psychiatric disorders is also well documented. Insulin has neuromodulatory
effects on important neurotransmitters; furthermore, insulin
secretion and insulin receptor sensitivity are shown to be
impaired in psychiatric disorders. Additionally, the existence
of a positive correlation between diabetes mellitus and
behavioral disorders like depression and schizophrenia is
also reported by several studies (reviewed in [12]).
According to previously mentioned evidences that show an
evident overlap between impairment in insulin signaling and
TLR activities in some brain pathologies and referring to
studies which showed that TLRs participate in the induction
of central as well as peripheral insulin resistance, this possibility raises that an interaction between insulin signaling and
TLR signaling might be involved in these pathologies. In
other words, these studies imply that a bidirectional association between TLRs and insulin signaling pathways may play a
role in the development and progression of these disorders. In
the following section, we will review the most important
pathways where interaction of the two pathways might occur.
Signaling Pathways Involved in the Interaction of Insulin
and TLR
PI3K/Akt Pathway
Phosphatidylinositide 3-kinases (PI3K) is a lipid kinase which
plays role in the regulation of different important cellular
processes such as cell growth, proliferation, differentiation,
motility, survival, and intracellular trafficking. This kinase
catalyzes the transfer of the γ-phosphate group of ATP to Dposition of phospho-inositide to form Ptd-Is (3, 4, 5) P3
(PIP3). PIP3 is an upstream activator of Akt (PKB) and a
number of other signaling elements [64, 65]. The PI3K/Akt
pathway is considered as the major integrator involved in
CNS insulin signaling, which takes part in different insulinmediated functions such as neuronal survival and synaptic
plasticity [66]. In addition, it has been demonstrated that a
common feature in different restorative approaches against
neurodegenerative disease models is the activation of the
PI3K/Akt pathway [67–69]. Furthermore, disturbance of this
pathway is shown to take part in the pathophysiology of
psychiatric disorders such as depression, schizophrenia, and
Mol Neurobiol
anxiety [70, 71]. On the other side, the PI3K/Akt pathway is
affected by and affects TLR signaling. Despite some controversies about the exact effect of PI3K/Akt on TLR activation,
this pathway is generally considered as a negative regulator
for TLR signaling pathway. In such a way, TLR activation
induces the PI3K/Akt pathway and PI3K/Akt then inhibits
TLR activity, and this negative feedback mechanism tends to
limit TLR overactivity [65, 72, 73]. This inhibitory effect of
the PI3K/Akt pathway on TLR activity is further confirmed
when the PI3K/Akt pathway is downregulated, and such
situation is associated with TLR-induced inflammatory responses. It has been shown that inhibition of the PI3K/Akt
pathway by wortmanin causes TLR-mediated cytokine production to be augmented [74–76]. In accordance with these observations, Bauerfeld et al. have shown that PI3K/Akt is required
for recovery from LPS-induced mitochondrial perturbation,
and inhibition of this pathway exacerbates LPS damage [77].
Disruption of PI3K/Akt signaling is also shown to be accompanied with increased responsiveness to LPS [78, 79]. These
studies raise the possibility that disruption of the PI3K/Akt
pathway, as can be seen in situations like insulin resistance,
could unbrake TLR activity and this could initiate a deteriorating feedback loop which exacerbates the situations (Fig. 3).
GSK3β
Glycogen synthase kinase 3β (GSK3β) is a serine-threonine
kinase which constitutively is active and is targeted by the
PI3K/Akt pathway. One of the most important inhibitors for
GSK3β activity is insulin-mediated PI3K/Akt pathway [80].
The importance of insulin-induced suppression of GSK3β is
well depicted in studies on diabetic animals, a situation that
insulin signaling is impaired and GSK3β is freed from suppression. It has been demonstrated that diabetic GSK3β
overactivation plays an essential role in adverse effects associated with diabetes [81]. GSK3β overactivation also plays an
important role in the development and progression of insulin
resistance, and inhibition of GSK3β is considered as a protective approach against developing insulin resistance [82]. It is
evident that existence of a precise balance between GSK3β
and insulin activity is a critical issue in normal physiology. In
addition to the previously mentioned relation between GSK3β
and insulin, substantive evidences are also available showing
that GSK3β is an important contributor in the pathology of
AD. GSK3β is one of the main kinases responsible for tau
hyperphosphorylation, and inhibition of GSK3β is shown to
ameliorate tau phosphorylation. Furthermore, GSK3β also
takes part in Aβ accumulation as well as learning and memory
deficits [83–85]. In such a way, involvement of GSK3β in the
pathophysiology of psychiatric disorders like depression and
schizophrenia also has been documented [86, 87].
On the other hand, numerous evidences both in the CNS
and extraneuronal tissues are also available showing that
GSK3β is an important mediator of TLR-mediated inflammatory responses [88, 89]. In such a way, inhibition of GSK3β
ameliorates the adverse effects of inflammation. Consistently,
it has been shown that LPS-induced release of cytokines by
glial cells is highly dependent on GSK3β activity [90]. The
promoting role of GSK3β in neuroinflammatory injuries is
further verified by results showing that neuroinflammatory
responses could be ameliorated by inhibitors for GSK3β
[91]. In addition to participation in the release of inflammatory
cytokines, other aspects of the CNS immune system such as
tolerance and sensitization are also affected by GSK3β. Consistently, it has been shown that that inhibition of GSK3β is
associated with a higher level of tolerance in astrocytes [92].
Besides the role of GSK3β in the TLR4-induced cytokine
release, this kinase also takes part in TLR4-mediated apoptosis [93].
IKK/NF-ĸB Pathway
IκB kinase/NF-κB (IKK/NF-κB) signaling pathway is the
main pathway which takes part in TLR signaling pathway.
As mentioned in earlier sections, activation of TLRs by appropriate ligands triggers two MyD88-dependent and
MyD88-independent pathways which both result in the activation of the IKK/NF-κB pathway. IKK/NF-κB activation
leads to the release of NF-κB and its translocation into the
nucleus where NF-κB induces the expression of different
cytokine genes such as TNF-α [94, 95]. Several lines of
evidences are available showing that activation of this pathway participates in the induction of insulin resistance either
directly or indirectly. In following paragraphs, insulin
disturbing pathways of IKK/NF-κB will be reviewed briefly.
Direct Induction of Insulin Resistance
Evidences have been published showing that IKK/NF-κB per
se can impair insulin signaling, and this insulin disturbing
function is mainly carried out via IKKβ-induced phosphorylation of IRS-1. Accordingly, Gao et al. have shown that
activated IKK directly phosphorylates IRS-1 at its serine
residue, and chemical inhibition of IKKβ is associated with
reduced serine phosphorylation of IRS-1 [94]. In another
study, it was demonstrated that mice lacking IKKβ are less
susceptible to diet-induced insulin resistance [96]. It has been
reported that the direct insulin disturbing role of IKK is done
through phosphorylation of ser-307/312 in mouse/human
IRS-1 protein, while in an indirect way, phosphorylation of
other serine residues is induced by IKKβ [97].
Indirect Induction of Insulin Resistance by IKK/NF-κB
PTP1B Protein tyrosine phosphatase 1 B (PTP1B) is a
member of the protein tyrosine phosphatase (PTP) family
Mol Neurobiol
Fig. 3 Schematic representation of the signaling pathways linking insulin and TLR signaling. See Fig. 1 for abbreviations
which catalyzes the dephosphorylation of tyrosinephosphorylated proteins. Since then, PTP1B is considered
as a negative regulator for insulin signaling [98]. It has
been reported that PTP1B takes part in the development of
insulin resistance both in neuronal and non-neuronal tissues [99, 100]. Consistently, mice lacking PTP1B are
shown to be more insulin sensitive [101]. Moreover, inhibition of neuronal PTP1B is shown to be accompanied
with improved insulin signaling, an observation which
fortifies the role of PTP1B in neuronal insulin resistance
[102].
PTP1B is one of the mediators employed by the IKK/
NF-κB pathway to induce insulin resistance [103]. In vivo
and in vitro evidences have shown that inflammation and
proinflammatory cytokines are involved in the regulation of
PTP1B. For example, in an experiment done on hypothalamic
organotypic culture, it was demonstrated that TNF-α, as a
transcriptional target as well as activator of the IKK/NF-κB
pathway, increased the expression of PTP1B [104]. Similar
results were also obtained from an in vivo experiment [105].
These effects of TNF-α are at least partly carried out via
the IKK/NF-κB pathway [104, 105]. Consistent with this
Mol Neurobiol
hypothesis, it has been shown that activation of NF-κB in
the hypothalamus and its subsequent expression of PTP1B
interfere with hypothalamus insulin signaling [103].
Interestingly, evidences are also available indicating that
brain PTP1B activity is also linked with major neurodegenerative diseases. Accordingly, Mody et al. have shown that in
genetic models of AD, the neuronal level of PTP1B is increased
and these animals were reported to be more susceptible to dietinduced insulin resistance [106]. Additionally, it has been demonstrated that PTP1B has a regulatory role in tyrosine phosphorylation of α-synuclein, and inhibition of this phosphatase was
shown to prevent cell death of dopaminergic neurons, in such a
way that inhibition of PTP1B in animal models of PD was also
demonstrated to improve their behavioral deficits [107].
Based on these reports showing a clear involvement of
PTP1B in the development of insulin resistance and its role in
neurodegenerative diseases in addition to activating the effects
of the IKK/NF-κB pathway on this phosphatase, a possibility is
raised that PTP1B could be a point of interaction between insulin
resistance and TLR-induced neuroinflammatory responses in
brain pathologies.
S6K1 Another signaling element employed by IKKβ to induce insulin resistance is S6K1 (p70S6K) [97]. S6K1 is a
downstream of the PI3K/Akt/mTOR pathway which participates in the growth-promoting functions of insulin signaling.
Besides that, S6K1 also plays an inhibitory role in insulin
signaling pathway. As when S6K1 is activated by insulin, it
phosphorylates IRS-1 on serine residues causing insulin signaling to be inhibited. This way provides a negative feedback
mechanism to control insulin actions [97, 108]. This S6K1mediated phosphorylation of IRS-1 is another way which
inflammatory pathways employ to induce insulin resistance.
Consistently, it has been shown that TNF-α could activate
S6K1 in an Akt-independent but IKKβ-dependent manner,
thereby TNF-α-mediated activation of S6K1 induces insulin
resistance via a mechanism that requires IKKβ [97].
So it seems that S6K1 is another possible point of interaction between insulin and TLR-induced inflammatory responses. In such a way, activation of TLR-induced activation
of the IKK/NF-κB pathway and its resulting release of TNF-α
can fortify the negative feedback loop in insulin signaling, and
by this way, TLR activation may take part in insulin disturbances seen in brain disorders.
MAPK
Mitogen-activated protein kinases pathway (MAPKs) are a
group of serine-threonine kinases playing roles in a variety of
cellular activities and are divided into three main subgroups
which are as follows: extracellular signal-regulated kinases
(ERKs), Jun N-terminal kinases (JNKs), and P38 MAPK
[109]. As mentioned in earlier sections, MAPKs are another
important signaling pathway which participates in TLRinduced inflammatory responses [45]. It has been shown that
inhibition of MEK1/2, p38, or JNK causes the LPS or flagellininduced overexpression of proinflammatory cytokines (IL-1β,
NO) to be inhibited [110]. In another study, Johnsen et al. have
shown that P38 is required for TLR-3-induced expression of
interferon-β [111]. It is believed that the type of agonists and
their sensing TLRs determine the relative importance of each
P38, JNK, or ERK in the TLR signaling pathway [110]. For
instance, while JNK, P38, and ERK play equal roles in TLR4induced responses, in TLR5-mediated response, JNK plays the
dominant role and TLR7-mediated gene regulation is more
dependent on P38 [110]. Besides participation in cellular response to stress stimuli like TLR activation, MAPK members
also play a significant role in the induction of insulin resistance
as much as some believe that JNK is the central mediator in the
development of insulin resistance [112]. Consistently, it has
been shown that inhibition of central JNK increases the hypothalamic insulin sensitivity [113]. JNK-induced development
of insulin resistance is carried out via phosphorylation of serine
residues of IRS [114, 115]. In such a way, another member of
MAPKs, ERK, also participates in the impairment of insulin
signaling, and inhibition of ERK activation by MEK inhibitor
is reported to prevent TNF-α-induced development of insulin
resistance [116]. Two mechanisms for ERK-induced insulin
resistance are reported: IRS-1 phosphorylation and negative
regulation of IRS-1 expression [117]. These reports about the
harmful effects of ERK are in contrast to the traditional view
about the survival effects of this kinase; it has been shown that
however transient activation of ERK serves to be neuroprotective but sustained activation of this kinase contributes in neuronal death, indicating that duration of ERK activity is a
determining factor in ERK activity [118–120]. Besides JNK
and ERK evidences are also available showing that P38 also
participates in the induction of insulin resistance, as it has been
depicted that TNF-α-induced insulin resistance in vascular
cells is carried out via the P38 pathway [121].
Besides these evidences about the participation of MAPKs
in insulin resistance, numerous reports have been published
which indicate that MAPKs also play important roles in
the pathology of neurodegenerative as well as psychiatric
disorders. For instance, it have been demonstrated that
activated forms of JNK, P38, and ERK are increased in
the susceptible neurons of AD patients [122]. Furthermore,
involvement of these MAPKs in different aspects of AD, like
tau hyperphosphorylation [123, 124], Aβ accumulation [125,
126], and Aβ-induced apoptosis [127], is also documented.
Similarly, participation of MAPK activity in the pathology of
Parkinson’s disease [128], anxiety, depression [129], and
schizophrenia [130] also has been demonstrated. Collectively,
these evidences lead us to assume that activation of MAPK
members in brain pathologies may be involved in the interaction of TLRs and insulin signaling pathway.
Mol Neurobiol
SOCS-3
Suppressor of cytokine signaling-3 (SOCS-3) is a member of
a larger family of SOCS proteins which are activated by a
variety of cytokines and TLRs, and then they inhibit the same
signaling pathways that lead to their induction. In this
way, they provide a negative feedback mechanism for
inflammatory responses [131]. Besides the regulatory role
of SOCS-3 proteins for cytokine signaling, this protein is
also involved in the induction of insulin resistance, and
the SOCS-3-mediated insulin disturbance is achieved via
targeting of IRS-1 and IRS-2 for proteosomal degradation
[132]. Consistently, it has been shown that insulin-induced
phosphorylation of insulin receptor, IRS and Akt are diminished by overexpression of SOCS-3 [133]. In addition,
SOCS-3 is also shown to take part in the induction of
neuronal insulin resistance, as it has been shown that
sensitivity to insulin is increased in neural cells with
conditional knockout of SOCS-3 [134]. Collectively, it
seems that SOCS-3 plays a dual role during inflammatory
responses. On one hand, its suppressor function on inflammatory responses could protect cells against the adverse
effects of inflammation. On the other hand, activation of
SOCS-3 by TLRs and cytokines could impair insulin
signaling. These results imply that SOCS-3 could be considered as another hypothetical point which TLRs could
interact with insulin signaling and promote the common
pathologies of the CNS.
Concluding Remarks
After several years of arduous work, showing a clear involvement of insulin signaling in the physiology and pathophysiology of CNS, elucidating the possible ways which ends in
disruption of insulin functions seems to be essential. In the
present work, we focused on the role of TLR activity and its
resulting neuroinflammation in the pathologies of the CNS
which are associated with insulin signaling disruption, and the
possible signaling points which could link insulin and TLR
signaling were reviewed. This could open a way to start more
specific researches to find the exact and relative participation
of these proposed ways in each condition.
Conflict of Interest The authors declare that they have no conflict of
interests.
References
1. Lucas SM, Rothwell NJ, Gibson RM (2006) The role of inflammation in CNS injury and disease. Br J Pharmacol 147(Suppl 1):S232–
S240. doi:10.1038/sj.bjp.0706400
2. Hanamsagar R, Hanke ML, Kielian T (2012) Toll-like receptor
(TLR) and inflammasome actions in the central nervous system.
Trends Immunol 33(7):333–342. doi:10.1016/j.it.2012.03.001
3. More SV, Kumar H, Kim IS, Song SY, Choi DK (2013) Cellular and
molecular mediators of neuroinflammation in the pathogenesis of
Parkinson’s disease. Mediat Inflamm 2013:952375. doi:10.1155/
2013/952375
4. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013)
Neuroinflammation and psychiatric illness. J Neuroinflammation
10:43. doi:10.1186/1742-2094-10-43
5. Nataf S (2009) Neuroinflammation responses and neurodegeneration in multiple sclerosis. Rev Neurol 165(12):1023–1028. doi:10.
1016/j.neurol.2009.09.012
6. Obulesu M, Jhansilakshmi M (2013) Neuroinflammation in
Alzheimer’s disease: an understanding of physiology and pathology. Int J Neurosci. doi:10.3109/00207454.2013.831852
7. Hanke ML, Kielian T (2011) Toll-like receptors in health and
disease in the brain: mechanisms and therapeutic potential. Clin
Sci (London, England: 1979) 121(9):367–387. doi:10.1042/
cs20110164
8. Shatz M, Menendez D, Resnick MA (2012) The human TLR innate
immune gene family is differentially influenced by DNA stress and
p53 status in cancer cells. Cancer Res 72(16):3948–3957. doi:10.
1158/0008-5472.can-11-4134
9. Konner AC, Bruning JC (2011) Toll-like receptors: linking inflammation to metabolism. TEM 22(1):16–23. doi:10.1016/j.tem.2010.08.007
10. Benomar Y, Gertler A, De Lacy P, Crepin D, Ould Hamouda H,
Riffault L, Taouis M (2013) Central resistin overexposure induces
insulin resistance through Toll-like receptor 4. Diabetes 62(1):102–
114. doi:10.2337/db12-0237
11. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A (2013)
Insulin in the brain: sources, localization and functions. Mol
Neurobiol 47(1):145–171. doi:10.1007/s12035-012-8339-9
12. Ghasemi R, Dargahi L, Haeri A, Moosavi M, Mohamed Z,
Ahmadiani A (2013) Brain insulin dysregulation: implication for
neurological and neuropsychiatric disorders. Mol Neurobiol 47(3):
1045–1065. doi:10.1007/s12035-013-8404-z
13. Libby P (2007) Inflammatory mechanisms: the molecular basis of
inflammation and disease. Nutr Rev 65(12 Pt 2):S140–S146
14. Cain D, Kondo M, Chen H, Kelsoe G (2009) Effects of acute and
chronic inflammation on B-cell development and differentiation. J
Investig Dermatol 129(2):266–277. doi:10.1038/jid.2008.286
15. Xiao BG, Link H (1998) Immune regulation within the central
nervous system. J Neurol Sci 157(1):1–12
16. Konnecke H, Bechmann I (2013) The Role of Microglia and
Matrix Metalloproteinases Involvement in Neuroinflammation
and Gliomas. Clin Dev Immunol 2013:914104. doi:10.1155/
2013/914104
17. Balistreri CR, Colonna-Romano G, Lio D, Candore G, Caruso C
(2009) TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases. J Clin Immunol 29(4):406–
415. doi:10.1007/s10875-009-9297-5
18. Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009)
Purinergic signalling in inflammation of the central nervous system.
Trends Neurosci 32(2):79–87. doi:10.1016/j.tins.2008.11.003
19. Husemann J, Loike JD, Anankov R, Febbraio M, Silverstein SC
(2002) Scavenger receptors in neurobiology and neuropathology:
their role on microglia and other cells of the nervous system. Glia
40(2):195–205. doi:10.1002/glia.10148
20. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010)
Mechanisms underlying inflammation in neurodegeneration. Cell
140(6):918–934. doi:10.1016/j.cell.2010.02.016
21. Streit WJ (2002) Microglia as neuroprotective, immunocompetent
cells of the CNS. Glia 40(2):133–139. doi:10.1002/glia.10154
22. Medzhitov R (2001) Toll-like receptors and innate immunity. Nat
Rev Immunol 1(2):135–145. doi:10.1038/35100529
Mol Neurobiol
23. McGettrick AF, O'Neill LA (2010) Localisation and trafficking of
Toll-like receptors: an important mode of regulation. Curr Opin
Immunol 22(1):20–27. doi:10.1016/j.coi.2009.12.002
24. Wang YC, Lin S, Yang QW (2011) Toll-like receptors in cerebral
ischemic inflammatory injury. J Neuroinflammation 8:134. doi:10.
1186/1742-2094-8-134
25. Liu T, Gao YJ, Ji RR (2012) Emerging role of Toll-like receptors in
the control of pain and itch. Neurosci Bull 28(2):131–144. doi:10.
1007/s12264-012-1219-5
26. Akira S (2006) TLR signaling. Curr Top Microbiol Immunol
311:1–16
27. Crack PJ, Bray PJ (2007) Toll-like receptors in the brain and their
potential roles in neuropathology. Immunol Cell Biol 85(6):476–
480. doi:10.1038/sj.icb.7100103
28. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition
and innate immunity. Cell 124(4):783–801. doi:10.1016/j.cell.
2006.02.015
29. Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13(5):
816–825. doi:10.1038/sj.cdd.4401850
30. Kenny EF, O'Neill LA (2008) Signalling adaptors used by Toll-like
receptors: an update. Cytokine 43(3):342–349. doi:10.1016/j.cyto.
2008.07.010
31. Lucas K, Maes M (2013) Role of the toll like receptor (TLR) radical
cycle in chronic inflammation: possible treatments targeting the
TLR4 pathway. Mol Neurobiol 48(1):190–204. doi:10.1007/
s12035-013-8425-7
32. Downes CE, Crack PJ (2010) Neural injury following stroke: are
Toll-like receptors the link between the immune system and the
CNS? Br J Pharmacol 160(8):1872–1888. doi:10.1111/j.14765381.2010.00864.x
33. Williamson RT (1901) On the treatment of glycosuria and diabetes
mellitus with sodium salicylate. Br Med J 1(2100):760–762
34. Feingold KR, Soued M, Staprans I, Gavin LA, Donahue ME,
Huang BJ, Moser AH, Gulli R, Grunfeld C (1989) Effect of tumor
necrosis factor (TNF) on lipid metabolism in the diabetic rat.
Evidence that inhibition of adipose tissue lipoprotein lipase activity
is not required for TNF-induced hyperlipidemia. J Clin Invest 83(4):
1116–1121. doi:10.1172/jci113991
35. Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose
expression of tumor necrosis factor-alpha: direct role in obesitylinked insulin resistance. Sci (New York, NY) 259(5091):87–91
36. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997)
Protection from obesity-induced insulin resistance in mice lacking
TNF-alpha function. Nature 389(6651):610–614. doi:10.1038/
39335
37. Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM,
Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti
MJ, Scherer PE, Summers SA (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires
saturated fatty acid-induced ceramide biosynthesis in mice. J Clin
Invest 121(5):1858–1870. doi:10.1172/jci43378
38. Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity
and metabolic disease. J Clin Invest 121(6):2111–2117. doi:10.
1172/jci57132
39. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006)
TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025. doi:10.1172/jci28898
40. Jang HJ, Kim HS, Hwang DH, Quon MJ, Kim JA (2013) Toll-like
receptor 2 mediates high-fat diet-induced impairment of vasodilator
actions of insulin. Am J Physiol Endocrinol Metab 304(10):E1077–
E1088. doi:10.1152/ajpendo.00578.2012
41. Hennige AM, Sartorius T, Lutz SZ, Tschritter O, Preissl H, Hopp S,
Fritsche A, Rammensee HG, Ruth P, Haring HU (2009) Insulinmediated cortical activity in the slow frequency range is diminished
in obese mice and promotes physical inactivity. Diabetologia
52(11):2416–2424. doi:10.1007/s00125-009-1522-5
42. Sartorius T, Lutz SZ, Hoene M, Waak J, Peter A, Weigert C,
Rammensee HG, Kahle PJ, Haring HU, Hennige AM (2012) Tolllike receptors 2 and 4 impair insulin-mediated brain activity by
interleukin-6 and osteopontin and alter sleep architecture. FASEB
J Off Publ Fed Am Soc Exp Biol 26(5):1799–1809. doi:10.1096/fj.
11-191023
43. Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E, Carvalho
DP, Carvalheira JB, Velloso LA (2011) Low-grade hypothalamic
inflammation leads to defective thermogenesis, insulin resistance,
and impaired insulin secretion. Endocrinology 152(4):1314–1326.
doi:10.1210/en.2010-0659
44. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE,
Tsukumo DM, Anhe G, Amaral ME, Takahashi HK, Curi R,
Oliveira HC, Carvalheira JB, Bordin S, Saad MJ, Velloso LA
(2009) Saturated fatty acids produce an inflammatory response
predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci
Off J Soc Neurosci 29(2):359–370. doi:10.1523/jneurosci.276008.2009
45. Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM,
Woodruff TM (2009) Toll-like receptors in ischemia-reperfusion
injury. Shock (Augusta, Ga) 32(1):4–16. doi:10.1097/SHK.
0b013e318193e333
46. Lee H, Lee S, Cho IH, Lee SJ (2013) Toll-like receptors: sensor
molecules for detecting damage to the nervous system. Curr Protein
Pept Sci 14(1):33–42
47. Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34(5):269–
281. doi:10.1016/j.tins.2011.02.005
48. Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, Lockett S,
Dunlop NM, Wang JM (2006) Activation of Toll-like receptor 2 on
microglia promotes cell uptake of Alzheimer disease-associated
amyloid beta peptide. J Biol Chem 281(6):3651–3659. doi:10.
1074/jbc.M508125200
49. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009)
CD14 and toll-like receptors 2 and 4 are required for fibrillar
A{beta}-stimulated microglial activation. J Neurosci Off J Soc
Neurosci 29(38):11982–11992. doi:10.1523/jneurosci.3158-09.
2009
50. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K (2008) Toll-like
receptor 4-dependent upregulation of cytokines in a transgenic
mouse model of Alzheimer’s disease. J Neuroinflammation 5:23.
doi:10.1186/1742-2094-5-23
51. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006)
Role of toll-like receptor signalling in Abeta uptake and clearance.
Brain J Neurol 129(Pt 11):3006–3019. doi:10.1093/brain/awl249
52. Richard KL, Filali M, Prefontaine P, Rivest S (2008) Toll-like
receptor 2 acts as a natural innate immune receptor to clear amyloid
beta 1-42 and delay the cognitive decline in a mouse model of
Alzheimer’s disease. J Neurosci Off J Soc Neurosci 28(22):5784–
5793. doi:10.1523/jneurosci.1146-08.2008
53. Landreth GE, Reed-Geaghan EG (2009) Toll-like receptors in
Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153.
doi:10.1007/978-3-642-00549-7_8
54. Cameron B, Landreth GE (2010) Inflammation, microglia, and
Alzheimer’s disease. Neurobiol Dis 37(3):503–509. doi:10.1016/j.
nbd.2009.10.006
55. Koenigsknecht-Talboo J, Landreth GE (2005) Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially
regulated by proinflammatory cytokines. J Neurosci Off J Soc
Neurosci 25(36):8240–8249. doi:10.1523/jneurosci.1808-05.2005
56. Dehay B, Bezard E (2011) New animal models of Parkinson’s
disease. Mov Disord Off J Mov Disord Soc 26(7):1198–1205
57. Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson’s
disease: a target for neuroprotection? Lancet Neurol 8(4):382–397.
doi:10.1016/s1474-4422(09)70062-6
Mol Neurobiol
58. Noelker C, Morel L, Lescot T, Osterloh A, Alvarez-Fischer D,
Breloer M, Henze C, Depboylu C, Skrzydelski D, Michel PP,
Dodel RC, Lu L, Hirsch EC, Hunot S, Hartmann A (2013) Toll like
receptor 4 mediates cell death in a mouse MPTP model of Parkinson
disease. Sci Rep 3:1393. doi:10.1038/srep01393
59. Panaro MA, Lofrumento DD, Saponaro C, De Nuccio F, Cianciulli
A, Mitolo V, Nicolardi G (2008) Expression of TLR4 and CD14 in
the central nervous system (CNS) in a MPTP mouse model of
Parkinson's-like disease. Immunopharmacol Immunotoxicol 30(4):
729–740. doi:10.1080/08923970802278557
60. Ros-Bernal F, Hunot S, Herrero MT, Parnadeau S, Corvol JC, Lu L,
Alvarez-Fischer D, Carrillo-de Sauvage MA, Saurini F, Coussieu C,
Kinugawa K, Prigent A, Hoglinger G, Hamon M, Tronche F,
Hirsch EC, Vyas S (2011) Microglial glucocorticoid receptors
play a pivotal role in regulating dopaminergic neurodegeneration
in parkinsonism. Proc Natl Acad Sci U S A 108(16):6632–6637.
doi:10.1073/pnas.1017820108
61. De Miranda J, Yaddanapudi K, Hornig M, Villar G, Serge R, Lipkin
WI (2010) Induction of Toll-like receptor 3-mediated immunity
during gestation inhibits cortical neurogenesis and causes behavioral
disturbances. mBio 1 (4). doi:10.1128/mBio.00176-10
62. Forrest CM, Khalil OS, Pisar M, Smith RA, Darlington LG, Stone
TW (2012) Prenatal activation of Toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, Nmethyl-D-aspartate receptors and neurogenesis markers in offspring. Mol Brain 5:22. doi:10.1186/1756-6606-5-22
63. McKernan DP, Dennison U, Gaszner G, Cryan JF, Dinan TG (2011)
Enhanced peripheral toll-like receptor responses in psychosis: further evidence of a pro-inflammatory phenotype. Transl Psychiatry
1:e36. doi:10.1038/tp.2011.37
64. Troutman TD, Bazan JF, Pasare C (2012) Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by
PI3K. Cell Cycle (Georgetown, Tex) 11(19):3559–3567. doi:10.
4161/cc.21572
65. Hazeki K, Nigorikawa K, Hazeki O (2007) Role of phosphoinositide
3-kinase in innate immunity. Biol Pharm Bull 30(9):1617–1623
66. van der Heide LP, Ramakers GM, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog
Neurobiol 79(4):205–221. doi:10.1016/j.pneurobio.2006.06.003
67. Gunjima K, Tomiyama R, Takakura K, Yamada T, Hashida K,
Nakamura Y, Konishi T, Matsugo S, Hori O (2013) 3,4Dihydroxybenzalacetone protects against Parkinson’s diseaserelated neurotoxin 6-OHDA through Akt/Nrf2/glutathione pathway.
J Cell Biochem. doi:10.1002/jcb.24643
68. Zhang L, Huang L, Chen L, Hao D, Chen J (2013) Neuroprotection
by tetrahydroxystilbene glucoside in the MPTP mouse model of
Parkinson’s disease. Toxicol Lett 222(2):155–163. doi:10.1016/j.
toxlet.2013.07.020
69. Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M
(2000) Insulin regulates soluble amyloid precursor protein release
via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J Off
Publ Fed Am Soc Exp Biol 14(7):1015–1022
70. Leibrock C, Ackermann TF, Hierlmeier M, Lang F, Borgwardt S,
Lang UE (2013) Akt2 deficiency is associated with anxiety and
depressive behavior in mice. Cell Physiol Biochem Int J Exp Cell
Physiol Biochem Pharmacol 32(3):766–777. doi:10.1159/
000354478
71. Zheng W, Wang H, Zeng Z, Lin J, Little PJ, Srivastava LK,
Quirion R (2012) The possible role of the Akt signaling pathway in schizophrenia. Brain Res 1470:145–158. doi:10.1016/j.
brainres.2012.06.032
72. Fukao T, Koyasu S (2003) PI3K and negative regulation of TLR
signaling. Trends Immunol 24(7):358–363
73. Gelman AE, LaRosa DF, Zhang J, Walsh PT, Choi Y, Sunyer JO,
Turka LA (2006) The adaptor molecule MyD88 activates PI-3 kinase
signaling in CD4+ T cells and enables CpG oligodeoxynucleotide-
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
mediated costimulation. Immunity 25(5):783–793. doi:10.1016/j.
immuni.2006.08.023
Guha M, Mackman N (2002) The phosphatidylinositol 3-kinaseAkt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277(35):32124–32132. doi:10.1074/jbc.
M203298200
Pahan K, Raymond JR, Singh I (1999) Inhibition of phosphatidylinositol 3-kinase induces nitric-oxide synthase in
lipopolysaccharide- or cytokine-stimulated C6 glial cells. J Biol
Chem 274(11):7528–7536
Park YC, Lee CH, Kang HS, Chung HT, Kim HD (1997)
Wortmannin, a specific inhibitor of phosphatidylinositol-3-kinase,
enhances LPS-induced NO production from murine peritoneal
macrophages. Biochem Biophys Res Commun 240(3):692–696.
doi:10.1006/bbrc.1997.7722
Bauerfeld CP, Rastogi R, Pirockinaite G, Lee I, Huttemann M,
Monks B, Birnbaum MJ, Franchi L, Nunez G, Samavati L (2012)
TLR4-mediated AKT activation is MyD88/TRIF dependent and
critical for induction of oxidative phosphorylation and mitochondrial transcription factor A in murine macrophages. J Immunol
(Baltimore, Md: 1950) 188(6):2847–2857. doi:10.4049/jimmunol.
1102157
Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S,
Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C (2009)
The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31(2):220–231. doi:10.
1016/j.immuni.2009.06.024
Chaurasia B, Mauer J, Koch L, Goldau J, Kock AS, Bruning JC
(2010) Phosphoinositide-dependent kinase 1 provides negative
feedback inhibition to Toll-like receptor-mediated NF-kappaB activation in macrophages. Mol Cell Biol 30(17):4354–4366. doi:10.
1128/mcb.00069-10
Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A (2009) Glycogen
synthase kinase 3: more than a namesake. Br J Pharmacol 156(6):
885–898. doi:10.1111/j.1476-5381.2008.00085.x
Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L (2009)
Inactivation of GSK-3beta by metallothionein prevents diabetesrelated changes in cardiac energy metabolism, inflammation,
nitrosative damage, and remodeling. Diabetes 58(6):1391–1402.
doi:10.2337/db08-1697
Liu Y, Tanabe K, Baronnier D, Patel S, Woodgett J, Cras-Meneur C,
Permutt MA (2010) Conditional ablation of Gsk-3beta in islet beta
cells results in expanded mass and resistance to fat feeding-induced
diabetes in mice. Diabetologia 53(12):2600–2610. doi:10.1007/
s00125-010-1882-x
Gong CX, Iqbal K (2008) Hyperphosphorylation of microtubuleassociated protein tau: a promising therapeutic target for Alzheimer
disease. Curr Med Chem 15(23):2321–2328
Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of
Alzheimer’s disease. J Neurochem 104(6):1433–1439. doi:10.1111/
j.1471-4159.2007.05194.x
King MR, Anderson NJ, Guernsey LS, Jolivalt CG (2013)
Glycogen synthase kinase-3 inhibition prevents learning deficits
in diabetic mice. J Neurosci Res 91(4):506–514. doi:10.1002/jnr.
23192
Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA
(2004) Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet 36(2):131–137. doi:10.1038/
ng1296
Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M,
Kennedy P, Dietz D, Covington H 3rd, Russo S, Neve R, Ghose S,
Tamminga C, Nestler EJ (2011) A novel role of the WNT-dishevelledGSK3beta signaling cascade in the mouse nucleus accumbens in a
social defeat model of depression. J Neurosci Off J Soc Neurosci
31(25):9084–9092. doi:10.1523/jneurosci.0039-11.2011
Mol Neurobiol
88. Beurel E, Michalek SM, Jope RS (2010) Innate and adaptive immune
responses regulated by glycogen synthase kinase-3 (GSK3). Trends
Immunol 31(1):24–31. doi:10.1016/j.it.2009.09.007
89. Hofmann C, Dunger N, Scholmerich J, Falk W, Obermeier F (2010)
Glycogen synthase kinase 3-beta: a master regulator of toll-like
receptor-mediated chronic intestinal inflammation. Inflamm Bowel
Dis 16(11):1850–1858. doi:10.1002/ibd.21294
90. Beurel E, Jope RS (2009) Lipopolysaccharide-induced interleukin6 production is controlled by glycogen synthase kinase-3 and
STAT3 in the brain. J Neuroinflammation 6:9. doi:10.1186/17422094-6-9
91. Yuskaitis CJ, Jope RS (2009) Glycogen synthase kinase-3 regulates
microglial migration, inflammation, and inflammation-induced
neurotoxicity. Cell Signal 21(2):264–273. doi:10.1016/j.cellsig.
2008.10.014
92. Beurel E, Jope RS (2010) Glycogen synthase kinase-3 regulates
inflammatory tolerance in astrocytes. Neuroscience 169(3):1063–
1070. doi:10.1016/j.neuroscience.2010.05.044
93. Li H, Sun X, LeSage G, Zhang Y, Liang Z, Chen J, Hanley G, He L,
Sun S, Yin D (2010) beta-arrestin 2 regulates Toll-like receptor 4mediated apoptotic signalling through glycogen synthase kinase3beta. Immunology 130(4):556–563. doi:10.1111/j.1365-2567.
2010.03256.x
94. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J
(2002) Serine phosphorylation of insulin receptor substrate 1 by
inhibitor kappa B kinase complex. J Biol Chem 277(50):48115–
48121. doi:10.1074/jbc.M209459200
95. Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like
receptors. Trends Mol Med 13(11):460–469. doi:10.1016/j.
molmed.2007.09.002
96. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M,
Shoelson SE (2001) Reversal of obesity- and diet-induced insulin
resistance with salicylates or targeted disruption of Ikkbeta. Sci
(New York, NY) 293(5535):1673–1677. doi:10.1126/science.1061620
97. Zhang J, Gao Z, Yin J, Quon MJ, Ye J (2008) S6K directly
phosphorylates IRS-1 on Ser-270 to promote insulin resistance in
response to TNF-(alpha) signaling through IKK2. J Biol Chem
283(51):35375–35382. doi:10.1074/jbc.M806480200
98. Tonks NK, Neel BG (2001) Combinatorial control of the
specificity of protein tyrosine phosphatases. Curr Opin Cell
Biol 13(2):182–195
99. Gonzalez-Rodriguez A, Mas Gutierrez JA, Sanz-Gonzalez S, Ros
M, Burks DJ, Valverde AM (2010) Inhibition of PTP1B restores
IRS1-mediated hepatic insulin signaling in IRS2-deficient mice.
Diabetes 59(3):588–599. doi:10.2337/db09-0796
100. Murillo-Cuesta S, Camarero G, Gonzalez-Rodriguez A, De La Rosa
LR, Burks DJ, Avendano C, Valverde AM, Varela-Nieto I (2012)
Insulin receptor substrate 2 (IRS2)-deficient mice show sensorineural hearing loss that is delayed by concomitant protein tyrosine
phosphatase 1B (PTP1B) loss of function. Mol Med (Cambridge,
Mass) 18:260–269. doi:10.2119/molmed.2011.00328
101. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy
AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC,
Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP (1999)
Increased insulin sensitivity and obesity resistance in mice lacking
the protein tyrosine phosphatase-1B gene. Sci (New York, NY)
283(5407):1544–1548
102. Picardi PK, Calegari VC, Prada PO, Moraes JC, Araujo E,
Marcondes MC, Ueno M, Carvalheira JB, Velloso LA, Saad MJ
(2008) Reduction of hypothalamic protein tyrosine phosphatase
improves insulin and leptin resistance in diet-induced obese rats.
Endocrinology 149(8):3870–3880. doi:10.1210/en.2007-1506
103. Yu IC, Lin HY, Liu NC, Sparks JD, Yeh S, Fang LY, Chen L, Chang C
(2013) Neuronal androgen receptor regulates insulin sensitivity via
suppression of hypothalamic NF-kappaB-mediated PTP1B expression.
Diabetes 62(2):411–423. doi:10.2337/db12-0135
104. Ito Y, Banno R, Hagimoto S, Ozawa Y, Arima H, Oiso Y (2012)
TNFalpha increases hypothalamic PTP1B activity via the
NFkappaB pathway in rat hypothalamic organotypic cultures.
Regul Pept 174(1–3):58–64. doi:10.1016/j.regpep.2011.11.010
105. Zabolotny JM, Kim YB, Welsh LA, Kershaw EE, Neel BG, Kahn
BB (2008) Protein-tyrosine phosphatase 1B expression is induced
by inflammation in vivo. J Biol Chem 283(21):14230–14241. doi:
10.1074/jbc.M800061200
106. Mody N, Agouni A, McIlroy GD, Platt B, Delibegovic M (2011)
Susceptibility to diet-induced obesity and glucose intolerance in the
APP (SWE)/PSEN1 (A246E) mouse model of Alzheimer’s disease
is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and
basal phosphorylation of S6 ribosomal protein. Diabetologia
54(8):2143–2151. doi:10.1007/s00125-011-2160-2
107. Choi HS, Liew H, Jang A, Kim YM, Lashuel H, Suh YH (2012)
Phosphorylation of alpha-synuclein is crucial in compensating for
proteasomal dysfunction. Biochem Biophys Res Commun 424(3):
597–603. doi:10.1016/j.bbrc.2012.06.159
108. Ginion A, Auquier J, Benton CR, Mouton C, Vanoverschelde JL,
Hue L, Horman S, Beauloye C, Bertrand L (2011) Inhibition of the
mTOR/p70S6K pathway is not involved in the insulin-sensitizing
effect of AMPK on cardiac glucose uptake. Am J Physiol Heart Circ
Physiol 301(2):H469–H477. doi:10.1152/ajpheart.00986.2010
109. Crowe DL, Shemirani B (2000) The transcription factor ATF-2
inhibits extracellular signal regulated kinase expression and proliferation of human cancer cells. Anticancer Res 20(5A):2945–2949
110. Peroval MY, Boyd AC, Young JR, Smith AL (2013) A critical role
for MAPK signalling pathways in the transcriptional regulation of
toll like receptors. PloS one 8(2):e51243. doi:10.1371/journal.pone.
0051243
111. Johnsen IB, Nguyen TT, Bergstrom B, Lien E, Anthonsen MW
(2012) Toll-like receptor 3-elicited MAPK activation induces stabilization of interferon-beta mRNA. Cytokine 57(3):337–346. doi:10.
1016/j.cyto.2011.11.024
112. Li H, Yu X (2013) Emerging role of JNK in insulin resistance. Curr
Diabetes Rev 9(5):422–428
113. Benzler J, Ganjam GK, Legler K, Stohr S, Kruger M, Steger J,
Tups A (2013) Acute inhibition of central c-Jun N-terminal
kinase restores hypothalamic insulin signalling and alleviates
glucose intolerance in diabetic mice. J Neuroendocrinol 25(5):
446–454. doi:10.1111/jne.12018
114. Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The cJun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of
Ser(307). J Biol Chem 275(12):9047–9054
115. Solinas G, Naugler W, Galimi F, Lee MS, Karin M (2006) Saturated
fatty acids inhibit induction of insulin gene transcription by JNKmediated phosphorylation of insulin-receptor substrates. Proc Natl
Acad Sci U S A 103(44):16454–16459. doi:10.1073/pnas.
0607626103
116. Engelman JA, Berg AH, Lewis RY, Lisanti MP, Scherer PE (2000)
Tumor necrosis factor alpha-mediated insulin resistance, but not
dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1
adipocytes. Mol Endocrinol (Baltimore, Md) 14(10):1557–1569
117. Tanti JF, Jager J (2009) Cellular mechanisms of insulin resistance:
role of stress-regulated serine kinases and insulin receptor substrates
(IRS) serine phosphorylation. Curr Opin Pharmacol 9(6):753–762.
doi:10.1016/j.coph.2009.07.004
118. Subramaniam S, Unsicker K (2010) ERK and cell death: ERK1/2 in
neuronal death. FEBS J 277(1):22–29
119. Zhuang S, Schnellmann RG (2006) A death-promoting role for
extracellular signal-regulated kinase. J Pharmacol Exp Ther
319(3):991–997. doi:10.1124/jpet.106.107367
120. Cheung EC, Slack RS (2004) Emerging role for ERK as a key
regulator of neuronal apoptosis. Sci Signal 2004(251):pe45
Mol Neurobiol
121. Li G, Barrett EJ, Barrett MO, Cao W, Liu Z (2007) Tumor necrosis
factor-alpha induces insulin resistance in endothelial cells via a p38
mitogen-activated protein kinase-dependent pathway. Endocrinology
148(7):3356–3363. doi:10.1210/en.2006-1441
122. Zhu X, Castellani RJ, Takeda A, Nunomura A, Atwood CS, Perry
G, Smith MA (2001) Differential activation of neuronal ERK, JNK/
SAPK and p38 in Alzheimer disease: the ‘two hit’ hypothesis. Mech
Ageing Dev 123(1):39–46
123. Dehvari N, Isacsson O, Winblad B, Cedazo-Minguez A, Cowburn
RF (2008) Presenilin regulates extracellular regulated kinase (Erk)
activity by a protein kinase C alpha dependent mechanism. Neurosci
Lett 436(1):77–80. doi:10.1016/j.neulet.2008.02.063
124. Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW (2002)
Activation of c-Jun N-terminal kinase and p38 in an Alzheimer’s
disease model is associated with amyloid deposition. J Neurosci Off
J Soc Neurosci 22(9):3376–3385
125. Cho HJ, Kim SK, Jin SM, Hwang EM, Kim YS, Huh K, MookJung I (2007) IFN-gamma-induced BACE1 expression is mediated
by activation of JAK2 and ERK1/2 signaling pathways and direct
binding of STAT1 to BACE1 promoter in astrocytes. Glia 55(3):
253–262. doi:10.1002/glia.20451
126. Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G,
Borsello T (2009) JNK regulates APP cleavage and degradation in a
model of Alzheimer’s disease. Neurobiol Dis 33(3):518–525. doi:
10.1016/j.nbd.2008.12.014
127. Xuan A, Long D, Li J, Ji W, Zhang M, Hong L, Liu J (2012)
Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s
disease. J Neuroinflammation 9:202. doi:10.1186/1742-2094-9-202
128. Pan J, Zhao YX, Wang ZQ, Jin L, Sun ZK, Chen SD (2007)
Expression of FasL and its interaction with Fas are mediated
129.
130.
131.
132.
133.
134.
by c-Jun N-terminal kinase (JNK) pathway in 6-OHDA-induced
rat model of Parkinson disease. Neurosci Lett 428(2–3):82–87.
doi:10.1016/j.neulet.2007.09.032
Wefers B, Hitz C, Holter SM, Trumbach D, Hansen J, Weber P, Putz
B, Deussing JM, de Angelis MH, Roenneberg T, Zheng F,
Alzheimer C, Silva A, Wurst W, Kuhn R (2012) MAPK signaling
determines anxiety in the juvenile mouse brain but depression-like
behavior in adults. PloS one 7(4):e35035. doi:10.1371/journal.pone.
0035035
Funk AJ, McCullumsmith RE, Haroutunian V, Meador-Woodruff
JH (2012) Abnormal activity of the MAPK- and cAMP-associated
signaling pathways in frontal cortical areas in postmortem brain in
schizophrenia. Neuropsychopharmacol Off Publ Am Coll
Neuropsychopharmacol 37(4):896–905. doi:10.1038/npp.2011.267
Kariko K, Weissman D, Welsh FA (2004) Inhibition of toll-like
receptor and cytokine signaling—a unifying theme in ischemic
tolerance. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood
Flow Metab 24(11):1288–1304. doi:10.1097/01.wcb.0000145666.
68576.71
Howard JK, Flier JS (2006) Attenuation of leptin and insulin signaling by SOCS proteins. TEM 17(9):365–371. doi:10.1016/j.tem.
2006.09.007
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008)
Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135(1):61–73. doi:10.
1016/j.cell.2008.07.043
Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H,
Torisu T, Chien KR, Yasukawa H, Yoshimura A (2004) Socs3
deficiency in the brain elevates leptin sensitivity and confers
resistance to diet-induced obesity. Nat Med 10(7):739–743. doi:
10.1038/nm1071