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Aberrancy in CNS Signals and Other Factors
Related to Altered Homeostasis, Obesity and Metabolic Syndrome
Senior Chief Medical Officer and Consultant, Department of Medicine, Hindu Rao Hospital and NDMC Medical College, India
Submission: September 25, 2018; Published: October 09, 2018
*Corresponding author:Vinod Nikhra, Senior Chief Medical Officer and Consultant, Department of Medicine, Hindu Rao Hospital and NDMC Medical College, India.
How to cite this article: Vinod Nikhra. Aberrancy in CNS Signals and Other Factors Related to Altered Homeostasis, Obesity and Metabolic Syndrome.
OAJ Gerontol & Geriatric Med. 2018; 4(4): 555645. DOI: 10.19080/OAJGGM.2018.04.555645
Introduction: ‘The Obese-Obese World’- The obesity and metabolic syndrome (MetS) are a global epidemic of such magnitude that the today’s health scenario can be summed up as the ‘Obese-obese World’*. Obesity and MetS deteriorate quality of life and alter course of various chronic diseases, and on their own, are risk factors for diabetes, hypertension, cardiovascular disease and stroke, neurological degenerative diseases and cancers. Modern day lifestyle drives for excess calorie intake, comparatively reduced energy expenditure and storage of surplus energy in adipose tissue, an accentuated evolutionary need to fill body nutrients stores, leading to obesity, appended by pathophysiological alterations termed MetS.
CNS Regulation of Energy Intake: Specialised neurons in hypothalamus and brainstem primarily regulate energy homeostasis, food intake and body weight, and integrate multiple peripheral metabolic inputs, such as nutrients, gut-derived hormones, and adiposity-related signals. There are several neuropeptides involved, including melanin concentrating hormone (MCH) and the orexins. An abnormal alteration in ghrelin and leptin levels can lead to weight gain and Obesity. Increase in adipose tissue leads to overproduction of leptin and hypothalamus becoming resistant to leptin action. The reward circuitry involves interactions between several systems including opioids, endocannabinoids, serotonin and dopamine. The obese individuals appear to have abnormalities in dopaminergic activity, and an imbalance in the brain circuits promoting reward seeking and those governing cognitive control leads to an overriding stimulus to feeding, even in the absence of an energy deficit. Dorsal striatum is hyperactive in obese and may contribute aberrancy of satiety signals. The genetics involving various mutations contributes up to 70% towards a person’s vulnerability to obesity.
Regulation of Energy Expenditure: Energy is consumed in processes of physical activity, basal metabolism, and adaptive thermogenesis, which are modulated by brain, especially hypothalamic melanocortin system. Brown adipose tissue (BAT) plays a major role in thermogenesis. Central regulation of BAT thermogenesis is dependent on sympathetic outflow to BAT. Norepinephrine released from sympathetic nerve terminals binds to β3-adrenergic receptors on adipocytes in BAT to promote enhanced thermogenesis. In addition, many hormonal and nutrient signals, such as glucose, insulin, leptin and GLP-1 also influence sympathetic outflow to BAT.
Conclusion Fallouts of Neuro signal Aberrancy: The obese subjects with BMI > 30 show atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus. MetS affects various cognitive domains including executive functioning, processing speed, and overall intellectual functioning. There is impaired vascular reactivity, endothelial dysfunction, neuro-inflammation, oxidative stress and altered brain metabolism.
The overweight and obesity are a global epidemic of such magnitude that the today’s health scenario can be summed up as the ‘Obese-obese World’ . Obesity and MetS deteriorate quality of life and alter course of various chronic diseases, and on their own, are risk factors for diabetes, hypertension, cardiovascular disease and stroke, neurological degenerative diseases and cancers. Modern day lifestyle drives for excess calorie intake, comparatively reduced energy expenditure and storage of surplus energy in adipose tissue, an accentuated evolutionary
need to fill body nutrients stores, leading to obesity, appended by pathophysiological alterations termed MetS (Figure 1). The pandemic of nutrition-related non-communicable diseases (NR-NCD) is due to an increased consumption of processed foods, saturated and total fats, sugar, and high caloric beverages . The current pandemic of NR-NCD has occurred in the setting a global reduction in physical activity . According to the World Health Organization, insufficient physical activity was one of the 10 leading risk factors for mortality, contributing to some 3.2 million deaths per year, and 69.3 million disability-adjusted life years in 2010 .
The specialised neurons in hypothalamus and brainstem
primarily regulate energy homeostasis, food intake and body
weight, and integrate multiple peripheral metabolic inputs, such
as nutrients, gut-derived hormones and signals from adipose
tissue . There are several neuropeptides involved, including
melanin concentrating hormone (MCH) and the orexins .
The reward circuitry involves interactions between several
systems including opioids, endocannabinoids, serotonin and
dopamine. The obese individuals appear to have abnormalities
in dopaminergic activity and an imbalance in the brain circuits
promoting reward seeking and those governing cognitive control
overriding stimulus to feeding . The increase in adipose tissue
leads to overproduction of leptin and hypothalamus becomes
relatively resistant to its action. Dorsal striatum is hyperactive
in obese and may contribute aberrancy of satiety signals. The
genetics involving various mutations may contribute up to 70%
towards a person’s vulnerability to obesity.
The Hypothalamus: The hypothalamus is regulator of
the autonomic nervous system (ANS), the circadian clock for
behavioral and sleep-wake functions, the neural centers of the
endocrine system, and the primary regulator of thirst and hunger.
It communicates with other regulating centers in the central and
peripheral nervous systems, including the prefrontal and insular
cortices, the amygdala and other limbic structures, the midbrain,
the pons, the medulla, and the vagus and glossopharyngeal
nerves. There are projections to and from hypothalamus,
brainstem, pons and cortical centers. The arcuate nucleus (AN)
contains orexigenic neurons co-expressing agouti-related protein
and neuropeptide Y (AgRP/NPY neurons) and anorexigenic
neurons co-expressing pro-opiomelanocortin and cocaine and
amphetamine-regulated transcripts (POMC/CART). AN play a
major role in regulation of food intake and calorie expenditure
(Figure 2). Being located outside the blood-brain barrier, it can
receive inputs from circulating nutrients and hormones. The
AgRP/NPY expressing neurons enhance appetite and weight
gain by γ-aminobutyric acid (GABA)-mediated tonic inhibition of
POMC/CART neurons including the suppression of anorexigenic
signals from neurons located in the parabrachial nucleus of the
pons. The anorexigenic inputs come from glutaminergic signals
originating in the nucleus tractus solitarius (NTS) in the medulla.
Both insulin and leptin suppress appetite by inhibiting AgRP/NPY
neurons. The orexigenic hormone ghrelin, produced by gastric
mucosa, enhances food intake by activating AgRP/NPY neurons.
The POMC/CART expressing neurons produce α-melanocyte
stimulating factor (α-MSF) which on binding to melanocortin-3
(MC3R) and melanocortin-4 (MC4R) receptors promotes energy
expenditure and suppresses food intake (8). These neurons are
inhibited by NPY and activated by leptin, serotonin, brain-derived
neurotrophic factor (BDNF), and glial-cell-derived growth and
differentiation neurotrophic factor 15 (GDF15). Glucagon-like
peptide-1 (GLP-1) expressing neurons in the medulla send
anorexigenic signals to the paraventricular nucleus (PVN).
Activation of the sympathetic nervous system by melanocortin
receptors in the ventromedial (VM) nucleus enhances energy
expenditure by increasing fatty acid utilization and thermogenesis
in skeletal muscle and brown adipose tissue.
Area Postrema, NTS and Vagus: The area postrema in
brainstem receives and integrates multiple metabolic signals,
including anorexigenic signals from leptin, cholecystokinin,
amylin, GLP-1, pancreatic peptide (PP) and peptide YY (PYY), and
orexigenic signals from ghrelin. This area projects to NTS, which
receives input from vagal afferent fibres located in the gastric
mucosa and intestinal wall and relays the signals to the parabrachial
nucleus (PBN) in the pons, which send anorexigenic signals to the
arcuate nucleus and central amygdala. GLP-1 expressing neurons
in the NTS relay anorexigenic signals to corticotrophin-releasing
hormone (CRH), nefstatin-1, and oxytocin-expressing neurons in
the PVN. GLP-1 receptor binding restricts feeding by excitatory
synaptic signals in paraventricular CRH neurons via a protein
kinase A-dependent signalling cascade. The BDNF receptor, TrkB,
is highly expressed in the area postrema, NTS and dorsal motor
nucleus of the vagus, and mediates the anorexigenic effects of
brainstem BDNF [8,9]. The vagal neurons expressing receptors
for gut-derived hormones play a significant role in appetite
regulation. GLP-1 binding induces an anorexigenic phenotype in
afferent vagal neurons, an effect that is down-regulated by ghrelin.
Further, the cholecystokinin-induced inhibition of food intake is
dependent on signaling from vagal afferent neurons. Importantly,
the vagal afferent neurons can change their phenotype and
express either orexigenic or anorexigenic receptors depending on
the availability of nutrients.
Midbrain and Limbic System: The taste aversions and taste
preferences are mediated in part by nuclei located in the central
amygdala. Smell sensation is also linked to appetite modulation
[10,11]. However, food reward signals are mediated primarily by
midbrain dopaminergic neurons projecting to the limbic system
and the prefrontal cortex which modulates eating behavior.
Further, growth hormone secretagogue receptors (GHSRs) in
dopaminergic neurons mediate ghrelin-induced feeding and foodreward
The Hypothalamus: In majority of obese persons, the ability
of the hypothalamus to control energy balance is altered . The
aberrant functioning is present at multiple levels like integration
of satiety signals and regulation of glucose and lipid metabolism. In
addition, the over-nutrition and adiposity leading to inflammatory
response alter the functioning of various hypothalamic nuclei
. The studies in rodents have documented that over-nutrition
causes resistance to the anorexic and thermogenic effects of leptin
due to reduced mRNA expression and transduction capabilities of
the leptin receptors in AN . The high fat diet reduces synapses
in POMC neurons. The diet-induced obesity is associated with a
failure of leptin to inhibit the orexigenic effects of AgRP neurons
. Humans with SNPs in the MC4R are morbidly obese,
hyperphagic, and have IR and elevated leptin levels. The obese
humans have reduced sensitivity to leptin’s anorexigenic effects.
Fasting ghrelin levels in children with the Prader-Willi syndrome
are elevated and appear to play a role in their insatiable appetite.
The BDNF levels are decreased in obese subjects with T2DM .
Area Postrema, NTS, PBN and Vagus: In rodents highcalorie
diet impairs anorexigenic signals in the caudomedial
nucleus of the NTS  and alters circadian clock genes .
Treatment with GDF15, binding to neurons in the NTS, the area
postrema, and the arcuate nucleus, decreases adiposity and
corrects metabolic function in diet-induced obese mice . The
administration of GLP-1 and GLP-1 agonists such as exendin-4
and liraglutide reduce food intake and weight in obese rodents
by inducing anorexigenic phenotype switching in afferent vagal
neurons. In humans, plasma GLP-1 levels are low in obese
individuals with normal or impaired glucose tolerance , and
administration of native GLP-1 and GLP-1 agonists have been
shown to reduce food intake and weight in obese humans .
In obese subjects, high intensity exercise increases GLP-1 levels
and reduces hunger scores . The therapeutic effects following
bariatric surgery involve the vagal NTS and vaso-vagal pathways
in restoring normal function to the pancreas - normalizing insulin
secretion, reducing glucagon production; liver - recovering insulin
sensitivity, reducing gluconeogenesis and free fatty acid release;
and gastrointestinal tract reducing ghrelin secretion, restoring
normal responses to nutrients, peptides, hormones .
Midbrain and Limbic System: The physical inactivity in
setting of obesity is associated with reductions in dopamine
receptor signaling in the meso-accumbens dopamine system.
Hedonic eating is the consumption of palatable foods beyond the
need-based energy requirements and prevalent in overweight and
obese individuals . The remarkable success of gastric bypass
surgeries in controlling overweight has been attributed, in part,
to a reduction in hedonic eating. Studies in humans have shown
that Roux-en-Y gastric bypass patients are less preoccupied with
eating and begin to prefer low calorie over high calorie more
palatable foods [25-27].
Energy balance and body weight are regulated by CNS, which
senses metabolic status from various humoral and neural signals
and controls energy intake . In the hypothalamus, stimulation
of leptin- and ghrelin-responsive pathways, including the central
melanocortin system, contributes to the maintenance of nearly
stable adipose tissue amount and body weight .
I. The CNS melanocortin (MC) system is implicated as a
mediator of the central effects of leptin, and reduced activity of the
CNS-MC system promotes obesity in both rodents and humans.
The CNS-MC receptor activation normally boosts metabolic rate. In
addition to α-MSH, several other hypothalamic neuropeptides are
known to be involved in the regulation of energy balance. These
include corticotropin-releasing hormone (CRH), neuropeptide Y
(NPY), and cocaine–amphetamine-related transcript (CART). The
activity of these neuropeptide systems is controlled by leptin, and
possibly by melanocortins as well .
II. The dysregulation of the pathways is a marker of changes
in energy balance . Ghrelin has appetite-inducing activities
and acts as an afferent signal to the hypothalamus. Leptin acts as
an afferent signal from adipose tissue to the hypothalamus, as a part of negative feedback loop regulating the size of energy stores
and energy balance. Ghrelin is negatively correlated with weight
and obese subjects have lower ghrelin levels than lean subjects,
consistent with a compensatory rather than causal role for ghrelin
in obesity. On the contrary, circulating leptin levels correlate with
proportion to adiposity, suggesting that obesity is associated with
insensitivity to leptin, i.e., leptin resistance. Apparently, ghrelin
and leptin operate as metabolic switch through hypothalamic/
pituitary axis . The appetite, energy expenditure, and basal
metabolic rate are linked [33,34].
III. The CNS significantly regulates adipose tissue mass by
acting on the metabolic pathways and on the adipose plasticity.
Innervation by autonomic nerves modulates glucose and fat
metabolism in adipose tissue and adipose tissue functions at
the cellular and molecular level like modulation of lipolysis/
lipogenesis, local insulin sensitivity of glucose and fatty acid
uptake, the expression levels of several adipokines in adipose
tissue, and the adipose tissue amount and cell-size. In general,
the sympathetic nervous system is related to catabolism and the
parasympathetic system to anabolism .
IV. The increased release of pro-inflammatory cytokines,
including TNF-α, is a key feature of the pathophysiology of
metabolic disorders. Adiposity induces an inflammatory response
in peripheral metabolic tissues. The metabolic inflammation or
meta-flammation, causes metabolic defects that underlie T2DM
and obesity. TNF-α is overexpressed in adipose tissue of obese
individuals and the elevated TNF-α levels cause peripheral IR. In
T2DM, elevated TNF-α levels trigger serine phosphorylation of
IRS-1 by stress kinases, which interferes with its ability to engage
in insulin receptor signaling and blocks the intracellular actions of
insulin. The blockade of TNF-α in obese mouse models results in
improved insulin sensitivity and glucose homeostasis. In the brain,
TNF-α is secreted mainly by microglial cells in response to trauma,
infection or abnormal accumulation of protein aggregates .
V. Lipids are structural elements of membranes or act as
signaling molecules regulating metabolic homeostasis through
many mechanisms. With increasing adiposity, lipid influx can
exceed the adipose tissue storage capacity, resulting in lipid
accumulation at ectopic sites such as liver and muscle. The
accumulation of lipids or generation of signaling intermediates
can interfere with immune regulation, causing a chronic lowgrade
metabolic inflammation, termed meta-flammation, which is
the hallmark of lip toxicity in metabolic diseases such as obesity
and diabetes, and occurs in several organs including adipose
tissue, liver, muscle, brain and gut, and influences several immunometabolic
a) The lipotoxicity and accumulation of lipid cause
deterioration of metabolic regulation by converging on
inflammatory and stress pathways.
b) Lipotoxicity can also lead to ROS production from
mitochondria and inflammasome activation.
c) The synthesis of DAGs and ceramides.
d) DAGs activate stress kinases, PKCs, and the NFκB
pathway, and ceramides activate JNK signaling. Both DAGs and
ceramides cause insulin resistance via inhibition of IRS1 and
e) Activation of TLR4 signaling, which leads to activation
of inflammasomes and induction of inflammatory gene
transcription factors interferon regulatory factor (IRF), NFκB,
f) Accumulation of oxidized cholesterol or cholesterol
crystals also leads to induction of TLR4, PKR, and stress kinase
(JNK and p38) signaling or inflammasome activation and proinflammatory
gene expression, which are central players in
The mechanisms underlying the harmful effects of excess lipid
flux are related in part to the impact of lipids on the biophysical
properties of cellular organelles. The lipid synthesis is dysregulated
in the ER, leading to changes in phospholipid composition of
the ER membrane. These changes cause disruption of calcium
signaling, prolonged ER stress, and decreased translation of ERassociated
proteins (Figure 3). Whereas, saturated fatty acids and
cholesterol loading increase ER stress and associated cell death.
ER stress responses also intersect with inflammatory pathways
via activation of numerous inflammatory kinases, such as JNK,
protein kinase R (PKR), and IKK, and activation of inflammatory
mediators and the inflammasome. Beyond the alteration of organelle function, lipotoxicity influences meta flammation
and hormone action via direct effects on intracellular signaling
pathways. Finally, lipids can influence cell fate and function
by engaging receptors on the cell surface or stress kinases
within the cytoplasm. Lipotoxicity plays an important role in
islet dysfunction. The chronic elevation of lipids leads to β-cell
failure together with inflammatory etiology. T2DM patients have
increased IL-1β expression and macrophage recruitment in the
islets. Also, the β-cell failure in T2DM may have an inflammatory
component that is compounded by lipotoxicity. In both humans
and preclinical models, obesity-induced inflammatory changes
are evident in the brain, and hypothalamic ER stress contributes
to defective insulin and leptin action.
i. Skeletal Muscle: High levels of circulating fatty acids
and triglycerides are associated with muscle insulin resistance.
In addition, adipocytes can accumulate in the muscle tissue.
The lipid-mediated changes during IR in muscle converge with
immune pathways and regulate inflammatory signaling.
ii. The heart has a robust capacity to utilize fatty acids for
metabolic and functional demands. However, a prolonged increase
in circulating fatty acids and triglycerides and accumulation of
pericardial adipose tissue can trigger inflammatory signaling in
the heart and cause cardiac dysfunction.
iii. The ingestion of high-fat diet leads to changes in the
gut microbiome, and a contributor to development of metabolic
disease. Gut-derived lipid signals such as N-acyl-phosphatidylethanol
amines (NAPEs) produced on high fat intake have impact
on immune-metabolic outcomes and the alterations in gut
microbiota influence neuroinflammation .
As meta flammation is the hallmark of chronic metabolic
disease, immunoregulatory or anti-inflammatory therapies can
help reduce lipid-induced inflammation and cellular dysfunction.
The ω-3 fatty acids have also been shown to inhibit metabolic
inflammation and alleviate insulin resistance. Additional beneficial
roles are attributed to ω-3 fatty acids through their metabolism
into resolvins and protectins. Because lipotoxicity impairs ER
function and leads to a prolonged unfolded protein response,
which can engage stress and inflammatory pathways. The use of
agents that alleviate ER stress, such as tauro-ursodeoxy-cholic acid
(TUDCA) and 4-phenylbutyric acid, has been tested in metabolic
contexts with beneficial results on liver and CNS function.
TUDCA treatment in experimental models of acute pancreatitis
and ischemia reperfusion in liver also demonstrated decreased
JNK activity along with attenuated inflammatory responses.
Interestingly, TUDCA treatment in humans also improved liver
and muscle insulin resistance warranting further clinical studies.
Obesity directly affects the glucose and energy metabolism
of the brain cells and through increased secretion of
pro-inflammatory agents like TNF-α, IL-1, IL-6 induces
neuroinflammation primarily in the hypothalamic area of the
brain. The overall effect is impairment of neuronal function and
internal molecular damage, which results in abnormal protein
deposits intracellularly or extracellularly or both, leading to
neurodegeneration (Figure 4). Obesity and neurodegenerative
diseases (NDDs) are linked by alterations in molecular pathways
such as P13K/Akt signaling pathway and IKKβ/NF-κB pathway,
which change genes expression profiles and activate or deactivate
molecular mediators, heralding the drift away from normal cellular
functioning. Concomitants with these alterations are oxidative
damage to cellular components and increased secretion of proinflammatory
factors such as TNFα, cytokines and interleukins
Impaired Glucose Homeostasis and CNS Physiology: Impaired
glucose tolerance precedes T2DM which in turn leads to
various neurodegenerative disorders. As compared to general
population, the increased risk of dementia is 50%–150% in those
with T2DM. Insulin holds important neurotrophic properties in
the brain. It is transported to the central nervous system through
the blood-brain barrier by a transport mechanism mediated by
insulin receptors. These receptors are chiefly localized in hippocampus,
entorhinal cortex and frontal which functions in learning,
memory and cognition. Visceral adiposity is a major cause of insu lin resistance. Visceral fat tissues due to their high metabolic rate
act as endocrine organs that secretes adipokines (e.g. leptin) and
cytokines (e.g. TNF-α, IL-6, heparin-binding epidermal growth
factor). Activation of proinflammatory pathways and secretion
of cytokines leads to insulin resistance. Insulin resistance is the
common pathophysiologic characteristic of obesity and glucose
intolerance affecting the membrane cation transport. The insulin
deficiency and resistance trigger neuronal death and neurodegeneration
due to the withdrawal of trophic factor, energy metabolism
deficits and inhibition of insulin-responsive gene expression.
Brain cells are unable to synthesize or store glucose; therefore, it
must be transported across the blood-brain-barrier. This is done
by Glucose Transporters like GLUT-1, GLUT-3 and GLUT-4. In condition
of glucose dysmetabolism, advanced glycation end products
(AGEs), start accumulating within the cells. AGEs glycated Aβ
which make these peptides more prone to aggregation, also AGEs
play a role in hyperphosphorylation of tau, and in formation of
senile plaques, tau hyperphosphorylation and subsequently, neurofibrillary
tangles, the hallmark for AD.
Initiation and Sustenance of Neuroinflammation: Neuroinflammation
is activation of innate immune response of brain
for protection of CNS against infections, injuries and disease, and
comprises of a complex series of reactions consisting of cellular
and molecular changes, activation of peripheral immune response,
initiation of intracellular signaling pathway, release of inflammatory
mediators leading to neuronal dysfunction and loss.
Neuroinflammation leads to neurodegeneration by activation of
IKKβ/NF-κB pathway, dysfunction of BBB and accumulation of
macrophages, astrocytes and microglia. Obesity facilitates systemic
inflammation as the hypertrophied adipocytes and immune
cells of adipose tissue lead to increased circulating levels of proinflammatory
cytokines like TNF-α, IL-6, IL-1β etc. IL-6 and IL-1β
have been shown to damage neuronal circuits involved in cognition
and memory. Thus, neuroinflammation can, thus, be considered
a consequence of obesity leading to neurodegeneration.
Over 50 adipokines are produced by adipocytes, out of
which leptin, autotoxin and adiponectin play predominant role
in neurodegeneration. Leptin, a 16KDa protein, is translated
from obese (ob) gene, and regulates appetite by primarily acting
on hypothalamic region. Leptin receptors are also expressed
in extra hypothalamic regions like amygdala, brain stem and
cerebellum. Leptin is neuroprotectant against oxidative stress
and cytotoxicity. Leptin has protective effects against 6-OHDA
(6-hydroxydopamine) toxicity in dopaminergic neurons and
preserves the functioning of the dopamine system. The reduced
leptin levels with obesity, increase in the risk of PD. The leptin
signaling is significantly decreased in the arcuate nucleus in
obese individuals  and has been negatively correlated
with AD pathology. Obesity has also been associated with the
accelerated aging process. Hypothalamus constitutes the major
CNS part affected by neuroinflammation. IKKβ/NF-κb has been
documented to trigger hypothalamic inflammation which in turn
leads to glucose intolerance, insulin resistance and impaired
insulin secretion. Activation of IKKβ/NF-κb pathway also affects
the differentiation of neuronal stem cells and impairs their
survival resulting in neurodegeneration.
Alterations in Signaling Pathways Leading to Neurodegeneration:
Insulin and Insulin Growth Factor 1 (IGF-1) are important
in brain glucose homeostasis and cell survival, and act
through the P13K-Akt signaling pathway. In normal insulin conditions,
insulin receptors (IR)/IGF-1Rs are activated in response
to oxidative stress, whereas glycogen synthasekinase-3 β (GSK-
3β) is inhibited. This is accompanied by increased production of
4-hydroxynonenal (4-HNE) for oxidative protection of neuronal
lipids and proteins. However, the impaired insulin/IR and IGF-1/
IGF-1R signaling result due to altered insulin and/or IGF-1 levels
in obesity and T2DM. The inflammatory response is mediated
by the activation of IKKb/NF-κB pathway. Hypothalamic inflammation
induced by IKKb/NF-κB causes glucose intolerance and
insulin resistance . The IKKβ pathway degrades IkB protein
and liberates NF-κB which localises to the nucleus and activates
transcription of inflammatory proteins. The Toll-like receptors
(TLRs) and cytokine receptors have been shown to mediate neuroinflammation
by activation of IKKb/NF-κB pathway through ER
stress and autophagy defects. These various pathway alterations
in obesity affect the normal brain functioning, lead to damaging
effects on the brain cells through oxidative stress, ER stress and
mitochondrial dysfunction, and cause cellular dysfunctions and
gradual neuronal loss .