Lexapro Weight Gain
Lexapro has been a popular antidepressant for several decades and Lexapro weight
gain has been overlooked by the healthcare industry. It is normal for 55% of those
taking Lexapro to experience weight gain. Unfortunately, 40.6 percent of the
people taking Lexapro will gain 7% or more weight, the health concerns are real.
(1)
Further studies are listed below but The Harper Method has one interest; helping
those that have Lexapro weight gain and losing the weight gain safely.
Who is this Lexapro weight gain solution method for?
It is for those who may or may not want to stay on Lexapro
It is also for those that are now off Lexapro
It is for those that have gained weight due to Lexapro
It is for those that have tried to diet and exercise and the Lexapro weight gain will
not come off
How this method works
You need to start reducing the activation of the JNK gene. The JNK gene is
associated with weight gain and all antidepressants induce the activation of the
JNK gene. Until you do this; all of the exercise and dieting in the world will be of
no use.
How this is done is simple. After 22 years of research two supplements have been
formulated in reduce the activation of the JNK1, JNK 2 and to slightly reduce the
activation of the JNK 3. Additionally, other proteins that reside upstream of the
JNK's need to be silenced and these are silenced with the supplements as well.
Foods; you should start eliminating foods with preservatives as your first diet
change.
Exercise; if you do not get any exercise, it is time to start with walking. At least 3
walks a week, with each walk for 20 minutes.
The two supplements setup your body to lose the weight gain caused by Lexapro
but you also need to do the normal things that help you lose weight; diet and
exercise.
I am assuming you have already tried diet and exercise without Lexapro weight
loss success.
Lexapro may have been a lifesaver for you but the weight gain is likely shortening
your life as well. High blood pressure and pre-diabetes are usually two of the
common physical problems associated.
After 22 years of research the solution for Lexapro weight gain is now available.
And it is simple.
Two nutritional supplements have been formulated to help reverse the Lexapro
weight gain. The first is the JNK 5 and the second is Optimum Solace.
(1) Jan-Feb 2015;37(1):46-8. doi: 10.1016/j.genhosppsych.2014.10.011. Epub 2014 Oct 31.
Weight gain and associated factors in patients using newer antidepressant drugs
Objective: The aim of the present study was to examine weight gain and its
association with clinical and sociodemographic characteristics in patients using
newer antidepressants.
Methods: The study had a cross-sectional design. A total of 362 consecutive
psychiatric patients taking antidepressant drugs for 6 to 36 months were included
in the study.
Results: The prevalence rate of weight gain was 55.2%; 40.6% of the patients had
a weight gain of 7% or more compared to the baseline. Overall, antidepressant use
was significantly related to increased body weight. Specifically, citalopram,
escitalopram, sertraline, paroxetine, venlafaxine, duloxetine and mirtazapine, but
not fluoxetine, were associated with significant weight gain. Multivariate logistic
regression analysis indicated that lower education status, lower body mass index at
the onset of antidepressant use and family history of obesity were independent
predictors of weight gain ≥7% compared to the baseline.
Conclusions: The study results suggest that patients who take newer
antidepressants might have significant problems related to body weight.
Keywords: Antidepressants; Body mass index; Weight gain.
(2) JNK at the crossroad of obesity, insulin resistance, and cell stress response
Background: The cJun-N-terminal-kinase (JNK) plays a central role in the cell
stress response, with outcomes ranging from cell death to cell proliferation and
survival, depending on the specific context. JNK is also one of the most
investigated signal transducers in obesity and insulin resistance, and studies have
identified new molecular mechanisms linking obesity and insulin resistance.
Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the
development of obesity and insulin resistance, JNK3 activity protects from
excessive adiposity. Furthermore, current evidence indicates that JNK activity
within specific cell types may, in specific stages of disease progression, promote
cell tolerance to the stress associated with obesity and type-2 diabetes.
Scope of review: This review provides an overview of the current literature on the
role of JNK in the progression from obesity to insulin resistance, NAFLD, type-2
diabetes, and diabetes complications.
Major conclusion: Whereas current evidence indicates that JNK1/2 inhibition may
improve insulin sensitivity in obesity, the role of JNK in the progression from
insulin resistance to diabetes, and its complications is largely unresolved. A better
understanding of the role of JNK in the stress response to obesity and type-2
diabetes, and the development of isoform-specific inhibitors with specific tissue
distribution will be necessary to exploit JNK as possible drug target for the
treatment of type-2 diabetes.
Keywords: Autophagy; Diabetes; Endoplasmic eeticulum stress; Inflammation;
MAPK; Oxidative stress.
(3) Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes
Obesity has been described as a global epidemic and is a low-grade chronic
inflammatory disease that arises as a consequence of energy imbalance. Obesity
increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely
clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids
(FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main
features of T2D, which are both aggravated with the progressive development of
hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds
to various cellular stress signals activated by cytokines, free fatty acids and
hyperglycemia, and is a key mediator in the transition between obesity and T2D.
Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is
therefore a potential target for T2D therapy.
Keywords: JNK; c-Jun N-terminal kinase; glucotoxicity; inflammation; insulin
resistance; lipotoxicity; obesity; type 2 diabetes.
(4) Adipocyte-Macrophage Cross-Talk in Obesity
Obesity is characterized by the chronic low-grade activation of the innate immune
system. In this respect, macrophage-elicited metabolic inflammation and
adipocyte-macrophage interaction has a primary importance in obesity. Large
amounts of macrophages are accumulated by different mechanisms in obese
adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte
chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway
also promotes more macrophage accumulation into the obese adipose tissue.
However, increased local extracellular lipid concentrations is a final mechanism
for adipose tissue macrophage accumulation. A paracrine loop involving free fatty
acids and tumor necrosis factor-alpha (TNF-alpha) between adipocytes and
macrophages establishes a vicious cycle that aggravates inflammatory changes in
the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-
1beta (IL-1beta) by macrophages; both adipocyte and macrophage induction by
toll like receptor-4 (TLR4) through nuclear factor-kappaB (NF-kappaB) activation;
free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase
(JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective
in macrophage accumulation and in the development of adipose tissue
inflammation. Old adipocytes are removed by macrophages through trogocytosis
or sending an "eat me" signal. The obesity-induced changes in adipose tissue
macrophage numbers are mainly due to increases in the triple-positive CD11b+
F4/80+ CD11c+ adipose tissue macrophage subpopulation. The ratio of M1-to-M2
macrophages is increased in obesity. Furthermore, hypoxia along with higher
concentrations of free fatty acids exacerbates macrophage-mediated inflammation
in obesity. The metabolic status of adipocytes is a major determinant of
macrophage inflammatory output. Macrophage/adipocyte fatty-acid-binding
proteins act at the interface of metabolic and inflammatory pathways. Both
macrophages and adipocytes are the sites for active lipid metabolism and signaling.
Keywords: C-C chemokine receptor 2 (CCR2); Chemokine (C-C motif) ligand 2
(CCL2); Free fatty acids; Hypoxia-inducible factor-1 alpha (HIF-1alpha); Insulin-
like growth factor-1 (IGF1); Interleukin-6 (IL-6); M1 macrophages; M2
macrophages; Monocyte chemoattractant protein-1 (MCP-1); NOD-like receptor
(NLR) family protein (NLRP3); Obesity; Toll like receptor 4 (TLR4); Tumor
necrosis factor-alpha (TNF-alpha); Visceral adipose tissue.
(5) The Role of JNk Signaling Pathway in Obesity-Driven Insulin Resistance
Obesity is not only closely related to insulin resistance but is one of the main
factors leading to the formation of Type 2 Diabetes (T2D) too. The c-Jun N-
terminal kinase (JNK) family is a member of the mitogen-activated protein kinase
(MAPK) superfamily. JNK is also one of the most investigated signal transducers
in obesity and insulin resistance. JNK-centric JNK signaling pathway can be
activated by growth factors, cytokines, stress responses, and other factors. Many
researches have identified that the activated phosphorylation JNK negatively
regulates insulin signaling pathway in insulin resistance which can be
simultaneously regulated by multiple signaling pathways related to the JNK
signaling pathway. In this review, we provide an overview of the composition of
the JNK signaling pathway, its regulation of insulin signaling pathway, and the
relationship between the JNK signaling pathway and other pathways in insulin
resistance.
Keywords: JNK signaling pathway; insulin resistance; obesity; type 2 diabetes.
(6) JNK expression by macrophages promotes obesity-induced insulin resistance
and inflammation
The cJun NH(2)-terminal kinase (JNK) signaling pathway contributes to
inflammation and plays a key role in the metabolic response to obesity, including
insulin resistance. Macrophages are implicated in this process. To test the role of
JNK, we established mice with selective JNK deficiency in macrophages. We
report that feeding a high-fat diet to control and JNK-deficient mice caused similar
obesity, but only mice with JNK-deficient macrophages remained insulin-sensitive.
The protection of mice with macrophage-specific JNK deficiency against insulin
resistance was associated with reduced tissue infiltration by macrophages.
Immunophenotyping demonstrated that JNK was required for pro-inflammatory
macrophage polarization. These studies demonstrate that JNK in macrophages is
required for the establishment of obesity-induced insulin resistance and
inflammation.
(7) The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation
Obesity is characterized by a state of chronic, low-grade inflammation. However,
excessive fatty acid release may worsen adipose tissue inflammation and
contributes to insulin resistance. In this case, several novel and highly active
molecules are released abundantly by adipocytes like leptin, resistin, adiponectin
or visfatin, as well as some more classical cytokines. Most likely cytokines that are
released by inflammatory cells infiltrating obese adipose tissue are such as tumor
necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), monocyte chemoattractant
protein 1 (MCP-1) (CCL-2) and IL-1. All of those molecules may act on immune
cells leading to local and generalized inflammation. In this process, toll-like
receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt)
signaling pathway, the unfolded protein response (UPR) due to endoplasmic
reticulum (ER) stress through hyperactivation of c-Jun N-terminal Kinase (JNK) -
Activator Protein 1 (AP1) and inhibitor of nuclear factor kappa-B kinase beta
(IKKbeta)-nuclear factor kappa B (NF-kappaB) pathways play an important role,
and may also affect vascular endothelial function by modulating vascular nitric
oxide and superoxide release. Additionally, systemic oxidative stress, macrophage
recruitment, increase in the expression of NOD-like receptor (NLR) family protein
(NLRP3) inflammasone and adipocyte death are predominant determinants in the
pathogenesis of obesity-associated adipose tissue inflammation. In this chapter
potential involvement of these factors that contribute to the adverse effects of
obesity are reviewed.
Keywords: Adipose tissue macrophages (ATMs); Autophagy; Ceramide;
Endoplasmic reticulum stress; Inducible nitric oxide synthase (iNOS);
Lipotoxicity; M1 adipose tissue macrophages; Macrophage migration inhibitory
factor (MIF); Monocyte chemoattractant protein 1 (MCP-1); Nuclear factor kappa
B (NF-kappaB); Obesity; Reactive oxygen species (ROS); Saturated fatty acid;
Toll-like receptor 4 (TLR4); Tumor necrosis factor alpha (TNF-alpha); Vascular
endothelial growth factor (VEGF).
(8) Human Protein Kinases and Obesity
The action of protein kinases and protein phosphatases is essential for multiple
physiological responses. Each protein kinase displays its own unique substrate
specificity, and a regulatory mechanism that may be modulated by association with
other proteins. Protein kinases are classified by the target amino acid in their
substrates. Some protein kinases can phosphorylate both serine/threonine, as well
as tyrosine residues. This group of kinases has been known as dual specificity
kinases. Unlike the dual specificity kinases, a heterogeneous group of protein
phosphatases are known as dual-specificity phosphatases. These phosphatases
remove phosphate groups from tyrosine and serine/threonine residues on their
substrate. Dual-specificity phosphatases are important signal transduction enzymes
that regulate various cellular processes in coordination with protein kinases. The
protein kinase-phosphoproteins interactions play an important role in obesity . In
obesity, the pro- and anti-inflammatory effects of adipokines and cytokines
through intracellular signaling pathways mainly involve the nuclear factor kappa B
(NF-kappaB) and the c-Jun N-terminal kinase (JNK) systems as well as the
inhibitor of kappaB-kinase beta (IKK beta). Impairment of insulin signaling in
obesity is largely mediated by the activation of the IKKbeta and the JNK.
Furthermore, oxidative stress and endoplasmic reticulum (ER) stress activate the
JNK pathway which suppresses insulin biosynthesis. Additionally, obesity-
activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-
induced protein kinase B phosphorylation by activating the ER stress effector,
activating transcription factor-4. Obese adults with vascular endothelial
dysfunction have greater endothelial cells activation of unfolded protein response
stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-
2alpha kinase (PERK) and activating transcription factor-6. The transcriptional
regulation of adipogenesis in obesity is influenced by AGC (protein kinase A
(PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic
oxidative stress and increase reactive oxygen species in adipocytes. Increase in
intracellular oxidative stress can promote PKC-beta activation. Activated PKC-
beta induces growth factor adapter Shc phosphorylation. Shc-generated peroxides
reduce mitochondrial oxygen consumption and enhances triglyceride
accumulation. Obesity is fundamentally caused by cellular energy imbalance and
dysregulation. Like adenosine monophosphate (AMP)-activated protein kinase
(AMPK) and mammalian target of rapamycin (mTOR), N-terminal Per-ARNT-
Sim (PAS) kinase are nutrient responsive protein kinases and important for proper
regulation of glucose metabolism in mammals at both the hormonal and cellular
level. Defective responses of AMPK to leptin may contribute to resistance to leptin
action on food intake and energy expenditure in obese states.
Keywords: Adenosine monophosphate (AMP)-activated protein kinase (AMPK);
Dual specificity kinases; Extracellular signal-regulated protein kinase (ERK);
Inhibitor of kappaB-kinase (IKK); Lipoapoptosis; Liver kinase B1 (LKB1); MAPK
phosphatases; Mammalian target of rapamycin (mTOR); Mitogen-activated protein
kinases (MAPK); N-terminal Per-ARNT-Sim (PAS) kinase (PASK); Protein
kinase B (Akt); Protein kinase-like endoplasmic reticulum (ER) eukaryotic
initiation factor-2alpha kinase (PERK); Protein kinases; Protein phosphatases; c-
Jun N-terminal kinase (JNK).
Lexapro Weight Gain
Lexapro has been a popular
antidepressant for several decades and
Lexapro weight gain has been
overlooked by the healthcare industry.
It is normal for 55% of those taking
Lexapro to experience weight gain.
Unfortunately, 40.6 percent of the
people taking Lexapro will gain 7%
or more weight, the health concerns
are real. (1)
Further studies are listed below but
The Harper Method has one interest;
helping those that have Lexapro
weight gain and losing the weight
gain safely.
Who is this Lexapro weight gain
solution method for?
It is for those who may or may not
want to stay on Lexapro
It is also for those that are now off
Lexapro
It is for those that have gained weight
due to Lexapro
It is for those that have tried to diet
and exercise and the Lexapro weight
gain will not come off
How this method works
You need to start reducing the
activation of the JNK gene. The JNK
gene is associated with weight gain
and all antidepressants induce the
activation of the JNK gene. Until you
do this; all of the exercise and dieting
in the world will be of no use.
How this is done is simple. After 22
years of research two supplements
have been formulated in reduce the
activation of the JNK1, JNK 2 and to
slightly reduce the activation of the
JNK 3. Additionally, other proteins
that reside upstream of the JNK's need
to be silenced and these are silenced
with the supplements as well.
Foods; you should start eliminating
foods with preservatives as your first
diet change.
Exercise; if you do not get any
exercise, it is time to start with
walking. At least 3 walks a week,
with each walk for 20 minutes.
The two supplements setup your body
to lose the weight gain caused by
Lexapro but you also need to do the
normal things that help you lose
weight; diet and exercise.
I am assuming you have already tried
diet and exercise without Lexapro
weight loss success.
Lexapro may have been a lifesaver for
you but the weight gain is likely
shortening your life as well. High
blood pressure and pre-diabetes are
usually two of the common physical
problems associated.
After 22 years of research the solution
for Lexapro weight gain is now
available. And it is simple.
Two nutritional supplements have
been formulated to help reverse the
Lexapro weight gain. The first is the
JNK 5 and the second is Optimum
Solace.
(1) Jan-Feb 2015;37(1):46-8.
doi:
10.1016/j.genhosppsych.2014.10.011.
Epub 2014 Oct 31.
Weight gain and associated factors in
patients using newer antidepressant
drugs
Objective: The aim of the present
study was to examine weight gain and
its association with clinical and
sociodemographic characteristics in
patients using newer antidepressants.
Methods: The study had a cross-
sectional design. A total of 362
consecutive psychiatric patients
taking antidepressant drugs for 6 to 36
months were included in the study.
Results: The prevalence rate of
weight gain was 55.2%; 40.6% of the
patients had a weight gain of 7% or
more compared to the baseline.
Overall, antidepressant use was
significantly related to increased body
weight. Specifically, citalopram,
escitalopram, sertraline, paroxetine,
venlafaxine, duloxetine and
mirtazapine, but not fluoxetine, were
associated with significant weight
gain. Multivariate logistic regression
analysis indicated that lower
education status, lower body mass
index at the onset of antidepressant
use and family history of obesity were
independent predictors of weight gain
≥7% compared to the baseline.
Conclusions: The study results
suggest that patients who take newer
antidepressants might have significant
problems related to body weight.
Keywords: Antidepressants; Body
mass index; Weight gain.
(2) JNK at the crossroad of obesity,
insulin resistance, and cell stress
response
Background: The cJun-N-terminal-
kinase (JNK) plays a central role in
the cell stress response, with
outcomes ranging from cell death to
cell proliferation and survival,
depending on the specific context.
JNK is also one of the most
investigated signal transducers in
obesity and insulin resistance, and
studies have identified new molecular
mechanisms linking obesity and
insulin resistance. Emerging evidence
indicates that whereas JNK1 and
JNK2 isoforms promote the
development of obesity and insulin
resistance, JNK3 activity protects
from excessive adiposity.
Furthermore, current evidence
indicates that JNK activity within
specific cell types may, in specific
stages of disease progression, promote
cell tolerance to the stress associated
with obesity and type-2 diabetes.
Scope of review: This review
provides an overview of the current
literature on the role of JNK in the
progression from obesity to insulin
resistance, NAFLD, type-2 diabetes,
and diabetes complications.
Major conclusion: Whereas current
evidence indicates that JNK1/2
inhibition may improve insulin
sensitivity in obesity, the role of JNK
in the progression from insulin
resistance to diabetes, and its
complications is largely unresolved. A
better understanding of the role of
JNK in the stress response to obesity
and type-2 diabetes, and the
development of isoform-specific
inhibitors with specific tissue
distribution will be necessary to
exploit JNK as possible drug target
for the treatment of type-2 diabetes.
Keywords: Autophagy; Diabetes;
Endoplasmic eeticulum stress;
Inflammation; MAPK; Oxidative
stress.
(3) Role of c-Jun N-terminal Kinase
(JNK) in Obesity and Type 2 Diabetes
Obesity has been described as a
global epidemic and is a low-grade
chronic inflammatory disease that
arises as a consequence of energy
imbalance. Obesity increases the risk
of type 2 diabetes (T2D), by
mechanisms that are not entirely
clarified. Elevated circulating pro-
inflammatory cytokines and free fatty
acids (FFA) during obesity cause
insulin resistance and ß-cell
dysfunction, the two main features of
T2D, which are both aggravated with
the progressive development of
hyperglycemia. The inflammatory
kinase c-jun N-terminal kinase (JNK)
responds to various cellular stress
signals activated by cytokines, free
fatty acids and hyperglycemia, and is
a key mediator in the transition
between obesity and T2D.
Specifically, JNK mediates both
insulin resistance and ß-cell
dysfunction, and is therefore a
potential target for T2D therapy.
Keywords: JNK; c-Jun N-terminal
kinase; glucotoxicity; inflammation;
insulin resistance; lipotoxicity;
obesity; type 2 diabetes.
(4) Adipocyte-Macrophage Cross-
Talk in Obesity
Obesity is characterized by the
chronic low-grade activation of the
innate immune system. In this respect,
macrophage-elicited metabolic
inflammation and adipocyte-
macrophage interaction has a primary
importance in obesity. Large amounts
of macrophages are accumulated by
different mechanisms in obese
adipose tissue. Hypertrophic
adipocyte-derived chemotactic
monocyte chemoattractant protein-1
(MCP-1)/C-C chemokine receptor 2
(CCR2) pathway also promotes more
macrophage accumulation into the
obese adipose tissue. However,
increased local extracellular lipid
concentrations is a final mechanism
for adipose tissue macrophage
accumulation. A paracrine loop
involving free fatty acids and tumor
necrosis factor-alpha (TNF-alpha)
between adipocytes and macrophages
establishes a vicious cycle that
aggravates inflammatory changes in
the adipose tissue. Adipocyte-specific
caspase-1 and production of
interleukin-1beta (IL-1beta) by
macrophages; both adipocyte and
macrophage induction by toll like
receptor-4 (TLR4) through nuclear
factor-kappaB (NF-kappaB)
activation; free fatty acid-induced and
TLR-mediated activation of c-Jun N-
terminal kinase (JNK)-related pro-
inflammatory pathways in CD11c+
immune cells; are effective in
macrophage accumulation and in the
development of adipose tissue
inflammation. Old adipocytes are
removed by macrophages through
trogocytosis or sending an "eat me"
signal. The obesity-induced changes
in adipose tissue macrophage
numbers are mainly due to increases
in the triple-positive CD11b+ F4/80+
CD11c+ adipose tissue macrophage
subpopulation. The ratio of M1-to-M2
macrophages is increased in obesity.
Furthermore, hypoxia along with
higher concentrations of free fatty
acids exacerbates macrophage-
mediated inflammation in obesity.
The metabolic status of adipocytes is
a major determinant of macrophage
inflammatory output.
Macrophage/adipocyte fatty-acid-
binding proteins act at the interface of
metabolic and inflammatory
pathways. Both macrophages and
adipocytes are the sites for active lipid
metabolism and signaling.
Keywords: C-C chemokine receptor
2 (CCR2); Chemokine (C-C motif)
ligand 2 (CCL2); Free fatty acids;
Hypoxia-inducible factor-1 alpha
(HIF-1alpha); Insulin-like growth
factor-1 (IGF1); Interleukin-6 (IL-6);
M1 macrophages; M2 macrophages;
Monocyte chemoattractant protein-1
(MCP-1); NOD-like receptor (NLR)
family protein (NLRP3); Obesity;
Toll like receptor 4 (TLR4); Tumor
necrosis factor-alpha (TNF-alpha);
Visceral adipose tissue.
(5) The Role of JNk Signaling
Pathway in Obesity-Driven Insulin
Resistance
Obesity is not only closely related to
insulin resistance but is one of the
main factors leading to the formation
of Type 2 Diabetes (T2D) too. The c-
Jun N-terminal kinase (JNK) family is
a member of the mitogen-activated
protein kinase (MAPK) superfamily.
JNK is also one of the most
investigated signal transducers in
obesity and insulin resistance. JNK-
centric JNK signaling pathway can be
activated by growth factors,
cytokines, stress responses, and other
factors. Many researches have
identified that the activated
phosphorylation JNK negatively
regulates insulin signaling pathway in
insulin resistance which can be
simultaneously regulated by multiple
signaling pathways related to the JNK
signaling pathway. In this review, we
provide an overview of the
composition of the JNK signaling
pathway, its regulation of insulin
signaling pathway, and the
relationship between the JNK
signaling pathway and other pathways
in insulin resistance.
Keywords: JNK signaling pathway;
insulin resistance; obesity; type 2
diabetes.
(6) JNK expression by macrophages
promotes obesity-induced insulin
resistance and inflammation
The cJun NH(2)-terminal kinase
(JNK) signaling pathway contributes
to inflammation and plays a key role
in the metabolic response to obesity,
including insulin resistance.
Macrophages are implicated in this
process. To test the role of JNK, we
established mice with selective JNK
deficiency in macrophages. We report
that feeding a high-fat diet to control
and JNK-deficient mice caused
similar obesity, but only mice with
JNK-deficient macrophages remained
insulin-sensitive. The protection of
mice with macrophage-specific JNK
deficiency against insulin resistance
was associated with reduced tissue
infiltration by macrophages.
Immunophenotyping demonstrated
that JNK was required for pro-
inflammatory macrophage
polarization. These studies
demonstrate that JNK in macrophages
is required for the establishment of
obesity-induced insulin resistance and
inflammation.
(7) The Pathogenesis of Obesity-
Associated Adipose Tissue
Inflammation
Obesity is characterized by a state of
chronic, low-grade inflammation.
However, excessive fatty acid release
may worsen adipose tissue
inflammation and contributes to
insulin resistance. In this case, several
novel and highly active molecules are
released abundantly by adipocytes
like leptin, resistin, adiponectin or
visfatin, as well as some more
classical cytokines. Most likely
cytokines that are released by
inflammatory cells infiltrating obese
adipose tissue are such as tumor
necrosis factor-alpha (TNF-alpha),
interleukin 6 (IL-6), monocyte
chemoattractant protein 1 (MCP-1)
(CCL-2) and IL-1. All of those
molecules may act on immune cells
leading to local and generalized
inflammation. In this process, toll-like
receptor 4
(TLR4)/phosphatidylinositol-3'-kinase
(PI3K)/Protein kinase B (Akt)
signaling pathway, the unfolded
protein response (UPR) due to
endoplasmic reticulum (ER) stress
through hyperactivation of c-Jun N-
terminal Kinase (JNK) -Activator
Protein 1 (AP1) and inhibitor of
nuclear factor kappa-B kinase beta
(IKKbeta)-nuclear factor kappa B
(NF-kappaB) pathways play an
important role, and may also affect
vascular endothelial function by
modulating vascular nitric oxide and
superoxide release. Additionally,
systemic oxidative stress, macrophage
recruitment, increase in the expression
of NOD-like receptor (NLR) family
protein (NLRP3) inflammasone and
adipocyte death are predominant
determinants in the pathogenesis of
obesity-associated adipose tissue
inflammation. In this chapter potential
involvement of these factors that
contribute to the adverse effects of
obesity are reviewed.
Keywords: Adipose tissue
macrophages (ATMs); Autophagy;
Ceramide; Endoplasmic reticulum
stress; Inducible nitric oxide synthase
(iNOS); Lipotoxicity; M1 adipose
tissue macrophages; Macrophage
migration inhibitory factor (MIF);
Monocyte chemoattractant protein 1
(MCP-1); Nuclear factor kappa B
(NF-kappaB); Obesity; Reactive
oxygen species (ROS); Saturated fatty
acid; Toll-like receptor 4 (TLR4);
Tumor necrosis factor alpha (TNF-
alpha); Vascular endothelial growth
factor (VEGF).
(8) Human Protein Kinases and
Obesity
The action of protein kinases and
protein phosphatases is essential for
multiple physiological responses.
Each protein kinase displays its own
unique substrate specificity, and a
regulatory mechanism that may be
modulated by association with other
proteins. Protein kinases are classified
by the target amino acid in their
substrates. Some protein kinases can
phosphorylate both serine/threonine,
as well as tyrosine residues. This
group of kinases has been known as
dual specificity kinases. Unlike the
dual specificity kinases, a
heterogeneous group of protein
phosphatases are known as dual-
specificity phosphatases. These
phosphatases remove phosphate
groups from tyrosine and
serine/threonine residues on their
substrate. Dual-specificity
phosphatases are important signal
transduction enzymes that regulate
various cellular processes in
coordination with protein kinases. The
protein kinase-phosphoproteins
interactions play an important role in
obesity . In obesity, the pro- and anti-
inflammatory effects of adipokines
and cytokines through intracellular
signaling pathways mainly involve
the nuclear factor kappa B (NF-
kappaB) and the c-Jun N-terminal
kinase (JNK) systems as well as the
inhibitor of kappaB-kinase beta (IKK
beta). Impairment of insulin signaling
in obesity is largely mediated by the
activation of the IKKbeta and the
JNK. Furthermore, oxidative stress
and endoplasmic reticulum (ER)
stress activate the JNK pathway
which suppresses insulin biosynthesis.
Additionally, obesity-activated
calcium/calmodulin dependent-
protein kinase II/p38 suppresses
insulin-induced protein kinase B
phosphorylation by activating the ER
stress effector, activating transcription
factor-4. Obese adults with vascular
endothelial dysfunction have greater
endothelial cells activation of
unfolded protein response stress
sensors, RNA-dependent protein
kinase-like ER eukaryotic initiation
factor-2alpha kinase (PERK) and
activating transcription factor-6. The
transcriptional regulation of
adipogenesis in obesity is influenced
by AGC (protein kinase A (PKA),
PKG, PKC) family signaling kinases.
Obesity may induce systemic
oxidative stress and increase reactive
oxygen species in adipocytes.
Increase in intracellular oxidative
stress can promote PKC-beta
activation. Activated PKC-beta
induces growth factor adapter Shc
phosphorylation. Shc-generated
peroxides reduce mitochondrial
oxygen consumption and enhances
triglyceride accumulation. Obesity is
fundamentally caused by cellular
energy imbalance and dysregulation.
Like adenosine monophosphate
(AMP)-activated protein kinase
(AMPK) and mammalian target of
rapamycin (mTOR), N-terminal Per-
ARNT-Sim (PAS) kinase are nutrient
responsive protein kinases and
important for proper regulation of
glucose metabolism in mammals at
both the hormonal and cellular level.
Defective responses of AMPK to
leptin may contribute to resistance to
leptin action on food intake and
energy expenditure in obese states.
Keywords: Adenosine
monophosphate (AMP)-activated
protein kinase (AMPK); Dual
specificity kinases; Extracellular
signal-regulated protein kinase
(ERK); Inhibitor of kappaB-kinase
(IKK); Lipoapoptosis; Liver kinase
B1 (LKB1); MAPK phosphatases;
Mammalian target of rapamycin
(mTOR); Mitogen-activated protein
kinases (MAPK); N-terminal Per-
ARNT-Sim (PAS) kinase (PASK);
Protein kinase B (Akt); Protein
kinase-like endoplasmic reticulum
(ER) eukaryotic initiation factor-
2alpha kinase (PERK); Protein
kinases; Protein phosphatases; c-Jun
N-terminal kinase (JNK).
