ISSN 19907508, Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2014, Vol. 8, No. 3, pp. 192202.

Pleiades Publishing, Ltd., 2014.

Original Russian Text L.S. Litvinova, E.V. Kirienkova, I.O. Mazunin, M.A. Vasilenko, N.S. Fattakhov, 2014, published in Biomeditsinskaya Khimiya.

Pathogenesis of Insulin Resistance in Metabolic Obesity

L. S. Litvinova1, E. V. Kirienkova, I. O. Mazunin, M. A. Vasilenko, and N. S. Fattakhov
Immanuel Kant Baltic Federal University, ul. Botkina 3, Kaliningrad, 236016 Russia
email: larisalitvinova@yandex.ru
Received May 6, 2013

AbstractThis review considers molecular mechanisms of insulin resistance developed under conditions of
metabolic inflammation; special attention is paid to analysis of the results of experimental and clinical studies
work aimed at identifying molecular targets for the development of new methods for prevention and treat
ment of insulin resistance.
Keywords: obesity, type 2 diabetes mellitus, metabolic syndrome, insulin resistance
DOI: 10.1134/S1990750814030093
1

INTRODUCTION

Obesity, type 2 diabetes, metabolic syndrome are

characterized by the development of inflammation in
adipose tissue and formation of tissue insulin resis
tance, primarily in adipose tissue, liver, and skeletal
muscles. Many studies revealed the causal relationship
between these pathological processes, but mecha
nisms responsible for their joining still remain unclear.
This review considers molecular mechanisms of insu
lin resistance developed under conditions of metabolic
inflammation; special attention is paid to analysis of
the results of experimental and clinical studies work
aimed at identifying molecular targets for the develop
ment of new methods for prevention and treatment of
insulin resistance.
1. MECHANISM OF INSULIN ACTION
Insulin is an anabolic hormone, which provides
normal metabolism and energy balance by inhibiting
glucose production by the liver and increasing its
absorption by muscles and adipose tissue. Inadequate
secretion of insulin and/or resistance to its action lead
to metabolic dysfunctions such as obesity, type 2 dia
betes mellitus (T2DM), and metabolic syndrome
(MS). In this regard, much attention is paid to the
metabolic and mitogenic effects of insulin [1, 2].
The insulin receptor is a tetramer consisting of
two extracellular subunits and two transmembrane
subunits. Subunits have affinity for insulin, while
subunits exhibit tyrosine kinase activity. Insulin
binds to the subunit; this causes conformational
changes and activation of subunit followed by subse
quent phosphorylation of insulin receptor tyrosine
residues [1, 2].
1 To whom correspondence should be addressed.

Activation of the insulin receptor results in its sub

sequent
binding
to
intracellular
proteins,
particularly to insulin receptor substrates 1 and 2
(IRS1 and IRS2) [1, 3, 4]. IRS1 activation is asso
ciated with glucose homeostasis and IRS2 in the reg
ulation of lipid metabolism, but the mechanism for
this specificity remains unclear [2].
Insulin action is mediated by three main signaling
cascades PI3K/Akt, Ras/MAPK, CAP/Cbl, which
include a large number of factors that regulate impor
tant cellular processes: glucose uptake into the cell,
protein synthesis, expression of genes involved in pro
liferation and differentiation [13, 5].
Phosphorylation of IRS Cterminal tyrosine resi
due by various kinases, particularly, phosphatidylinos
itol 3kinase (PI3K), results in formation of certain
binding sites for proteins containing a Srchomology
(SH2) domain. PI3K, consisting of catalytic subunit
(p110) and regulatory (p85) subunit, is an important
signaling molecule, which acts as an important link in
the metabolic effects of insulin. Binding of the
p85 subunit to the IRS phosphorylated tyrosine resi
due leads to activation of the catalytic activity of the
p110 subunit, followed by increased content of phos
phatidylinositol3,4bisphosphate (PIP2), and phos
phatidylinositol3,4,5trisphosphate (PIP3). Down
stream components of the PI3K signaling pathway
include several serine/threonine type kinases involved
(PDK1, Akt, p70S6 K, GSK3). These kinases are
involved in realization of such important biological
effects of insulin, as recruitment of the glucose trans
porter4 (Glucose transporter type 4, GLUT4) from
intracellular vesicles to the plasma membrane, protein
and glycogen synthesis, inhibition of apoptosis (Fig. 1)
[6, 7].
The CAP/Cbl signaling cascade is the second
important cascade (after PI3K/Akt); it begins with

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PATHOGENESIS OF INSULIN RESISTANCE IN METABOLIC OBESITY

Insulin

Glucose

193
Insulin

Insulin receptor

Insulin receptor

CrK

P P P P
PL3K
P
Shc P
IRS1/2
P
P
P
Grb2
P SHP2
Sos

P
C3G

Glucose
uptake

P P

CAP
Cbl
APS

PDK1
GDPTC10 GTPTC10

GTPras

GDPras GLUT expression

Translocation

Insulin signal
pathway feedback
Cascade mediated
by mitogenactivated
protein kinases

Growth
and
differentiation

PKC/l

GLUT4

Akt

p90rsk
P
p70S6K

Glycogen synthase

PP1

(inactive form)

GSK3

Glycogen synthase
(active form)

Protein
synthesis

GLUT4

Glycogen
synthesis
Fig. 1. The main pathways of the insulin signaling cascade. GLUT1 and 4: glucose transporter1 and 4; Grb2: isoform 2 growth
factor binding protein (growth factor binding receptor2); GSK3: glycogen synthase kinase3; IR: insulin receptor; IRS1
and 2: insulin receptor substrate1 and 2; MAPK: mitogenactivated protein kinase; PDK1: phosphoinositidedependent
kinase1; PIP2: phosphatidylinositol bisphosphate; PI3: phosphatidylinositol trisphosphate; P: phosphate; PKC: protein kinase
C; PP1: phosphoprotein phosphatase1; p70S6K: protein 70 S6 kinase; p70S6K and p90rsk: protein 90 ribosomal S6 kinase; Shc:
Src homology collagen; SHP2: phosphatase with Src homology 2 domain; SoS: protein that promotes the dissociation of gua
nine nucleotide complexes with Ras (Son of Sevenless) (adapted from [1]).

substrate capture by the activated insulin receptor and

subsequent phosphorylation of Cbl tyrosine residues
[2]. Cb1 interacts with Cb1associated protein (CAP)
via SH3 domain and flotilin, a component of the lipid
raft (via socalled sorbic domains). The CrkII/C3G
complex then binds to Cbl phosphorylated tyrosine
residues and thus activates C3G, which exchanges
GDP for GTP in the TC10 signaling protein. TC10
belongs to the Rhofamily of small GTPases, interact
ing with the cytoskeleton [8]. Participation of actin in
GLUT4 translocation to the plasma membrane is
regulated by small Gprotein, TC10 and TC10 by
exocyst assembly and PIP3 formation. Microtubule
proteins (KIF5b kinesins and KIF3) also facilitate
insulinmediated translocation of GLUT4 to the
plasma membrane [1, 9].
The cascade mediated by mitogenactivated pro
tein kinase (MAPK), begins with the interaction of
Shc (Src homology collagen) and the insulin receptor;

binding of Grb2 (growth factor receptor binding2)

with Shc or IRS1 and formation of a complex
Grb2/SoS (Son of Sevenless) in the plasma membrane
[10]. The system of Grb2 and SoS adapters activates
Ras protein, belonging to the superfamily of small
GTPbinding proteins [11]. Ras is a socalled molec
ular trigger; its mutations are found in many types of
tumors so that it may be referred to oncogenes. SOS
protein causes Ras conversion into an active GTP
form, whereas the opposite process (GTP hydrolysis
and Ras conversion into the inactive form, GDPRas)
is controlled by GAP, a GTPase activator protein
[11, 22]. Subsequent insulin signal transduction from
Ras to intracellular processes involves the
Raf/MEK/MAPK cascade, which regulates cell pro
liferation, differentiation, and cell growth [12], as well
as glycogen synthesis and GLUT4 translocation from
cytoplasm onto the membrane (Fig. 1) [13].

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Impaired activity of proteins involved in the insulin

signaling pathways results in the development of insu
lin resistance (IR) [14].
IRS phosphorylation by such downstream kinases
(located after PI3K) as the Akt/PKB, GSK3,
p70S6K, and also by protein kinases of other signaling
pathways such as 5'AMPactivated protein kinase
(AMPK), protein kinase C (PKC), cJunNH2ter
minal protein kinase (JNK), inhibitor of kappa B
kinase (IKK) can be performed on many of
serine/threonine residues [1, 2]. In general, such
phosphorylation inhibits IRS1 function and pro
motes its degradation, attenuation of the interaction
with the insulin receptor or association with
SH2 domains. Proinflammatory cytokines (tumor
necrosis factor (TNF), interleukin1 , and 6
(IL1, IL 6)), reactive oxygen species (ROS), free
fatty acids (FFA), leptin, adiponectin, endothelin1,
and other adipose tissue metabolites may function as
activators of the above considered protein kinases; this
results in impairments of insulin signal transmission
[2, 15] and the development of IR.
2. PATHOGENESIS OF INSULIN
RESISTANCE (IR)
IR occurs when insulinsensitive tissues, primarily
skeletal muscles, adipose tissue, and liver, lose their
ability to respond adequately to this hormone [16].
However, the exact mechanisms involved in the devel
opment of IR are not fully understood [17]. Much
attention is paid to improving the level of free fatty
acids (FFA), chronic hyperglycemia (CHG), develop
ment of subclinical chronic inflammation in adipose
tissue, oxidative and metabolic stress, altered gene
expression and mitochondrial dysfunction [18, 19].
2.1. Effect of Oxidative Stress on the Development
of Insulin Resistance
Intracellular redox reactions are precisely regu
lated in the body. ROS are involved in important bio
logical reactions; however their excessive production
and accumulation may lead to oxidative stress [2, 20,
21]. Thus, IR is accompanied by impaired metabolism
of ROS leading to the development of oxidative stress
[22].
Good evidence exists that oxidative stress is one of
the causes of muscle disorders contributing to forma
tion of IR. In transgenic mice expressing human ubiq
uitin ligase E3, it was demonstrated that decreased
superoxide degradation associated with impaired
activity of superoxide dismutase1 (SOD1) was
accompanied by development of oxidative stress and
muscle dysfunction (atrophy and sclerosis) [23].
Importance of ROS and activation of lipid peroxi
dation (LPO) in pathogenesis of T2DM complica
tions is unquestionable. The leading role of hypergly
cemia in the initiation and potentiation of ROS gener

ation has been demonstrated in experimental models

and in clinical studies [24].
There is clear evidence that damage of cells of
islets of Langerhans and consequently impaired insu
lin secretion, may be associated with activation
of hyperglycemiamediated oxidative stress [25]. The
cells are characterized by low expression of antioxi
dant enzymes; this results in the accumulation of ROS
activating serine/threonine kinases, particularly, JNK.
Inhibition of JNK in the mouse T2DM model
restored the function of cells, decreased IR, and
improved glucose tolerance [26].
As mentioned previously, some of the serine/threo
nine kinases (e.g. JNK, PKC, GSK3, NFB, and
p38), activated during oxidative stress, mediate
expression of proinflammatory molecules such
as TNF, IL6, macrophage chemoattractant pro
tein1 (MCP1), etc. [15] which, in turn, stimulate
subsequent ROS production. Realization of this sce
nario forms a positive feedback mechanism and the
process becomes selfsustaining with a tendency to
progression. ROS can alter vascular cell infiltration
and endothelial function by influencing the functional
state of adhesion molecules such as intercellular adhe
sion molecule1 (ICAM1) and vascular cell adhesion
molecule1 (VCAM1) [27, 28].
It is interesting that during starvation, stress, and
other excessive stress conditions IR provides fat accu
mulation and reduces oxidative stress, especially in
muscles and adipocytes [26].
2.2. The Effect of Adipose Tissue Inflammation
on the Development of IR
Inflammation is a well coordinated process; it
develops tissues in response to their injury due to
exposure to infectious and noninfectious agents. It is
known that the inflammatory response is triggered by
pathogen molecules recognized by cells of the
immune system (MAMPsmicrobial associated
molecular patterns), as well as by molecules which can
initiate the formation of immune memory response to
noninfectious inflammatory origin (DAMPSdam
ageassociated molecular patterns). Inflammation
inducers bind to appropriate receptors and activate the
biological response in resident cells, mainly macroph
ages and mast cells. These cells are directly or indi
rectly act on the vascular wall and immune system
cells, thereby mediating exudation and migration [29].
Some receptors represent sensors of damage or the
presence of infection. These include tolllike receptor
(TLRs), Clectin receptors, purinergic receptors,
receptor for advanced glycation endproducts
(RAGE), nucleotidebinding oligomerization domain
(NOD), and cytoplasmic RLRs receptors known as
retinoic acidinducible geneI (RIGI)like receptors.
Receptor interaction with corresponding ligands
results in activation of protein kinases JNK and IB

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(Inhibitor of kappa B) kinase (IKK) complex, which is

accompanied by changes in the activity of transcrip
tion factors, expression of cytokines, chemokines,
adhesion molecules and an overall increase of the
inflammatory response.
Activation of proinflammatory mechanisms is also
typical for those disorders that are secondary to obe
sity: IR and atherosclerosis [30]. Increased production
of inflammatory mediators in many tissues, including
the adipose tissue, liver, pancreas, skeletal muscle, and
hypothalamus registered in obese individuals [31] sug
gests the development of subclinical inflammation,
also known as the metabolic inflammation [32]. For
example, in adipose tissue of obese individuals
increased production of proinflammatory mediators
(TNF, IL1, IL6, IL8, transforming growth fac
tor (TGF), and nerve growth factor (NGF), as
well as formation of acute phase proteins (plasmino
gen activator inhibitor1, haptoglobin and plasma
amyloid A) in the liver have been detected [30, 31, 33].
Interestingly, IL6 is an essential factor for increas
ing the pancreatic cell mass in mice in response to a
highcalorie diet. Elevated circulating levels of IL6
increase plasma incretin, known as glucagonlike pep
tide1 (GLP1), insulin secretion, and glucose toler
ance. Furthermore, IL6 induces of GLP1 secretion
by enteric (intestinal) Lcells and pancreatic cells
[34, 35].
At the same time, the MS patients have dramati
cally reduced serum adiponectin, which inversely cor
relates with high content of acute phase Creactive
protein (CRP). The latter is able to form new athero
sclerotic plaques in the intima thus increasing proba
bility for rupture of blood vessels [31, 33, 36]. Elevated
CRP levels in the blood of MS patients are mediated
by the ability of adipose tissue to maintain increased
synthesis of inflammatory mediators (IL6, TNF,
plasminogen activator inhibitor1 (PAI1)), which are
stimulants of CRP production by the liver cells [36
38]. Our group found that surgical correction of obe
sity, laparoscopic gastric bypass surgery (LGS), leads
to normalization of serum levels of CRP; this may
indicate the interruption of chronic inflammation [37,
38].
However, unlike other diseases, associated with the
development of inflammation, little data are available
on inductors and receptors involved in inflammation
in obesity. Several hypotheses have been proposed to
explain the initial activation and accumulation of leu
kocytes in tissues (mainly in adipose tissue). They
consider DAMPS molecules, formed after adipocyte
destruction; increased FFA levels due to increased rate
of lipolysis; hypoxiainducible factor1 (HIF1),
which controls the production of proinflammatory
proteins and chemokines by adipocytes as the main
initiators of the inflammatory process [30, 39] (Fig. 2).
TLRs may be another possible pathogenetic link
between IR development and inflammation. These

195

transmembrane receptors are essential components of

innate immunity [40]. Adipocytes do express almost
all known TLRs. TLR2 and TLR4 play an important
role in the pathogenesis IR in diabetes [41]. In
C3H/HeJ mice with a mutation in the TLR4 gene adi
pose tissue, liver, and muscles preserved insulin sensi
tivity under conditions of a highcalorie diet. In turn,
activation of cytokine and chemokine production by
adipocytes and macrophages mediated by stimulation
of TLR2 and TLR4 was accompanied by the devel
opment of diabetes in mice [42]. Dasu et al. [41] found
a significant increase in the expression of TLR2 and
TLR4 in monocytes in T2DM patients. Koopet et al.
[43] demonstrated increased production of IL6 and
macrophage chemoattractant protein1 (MCP1)
during activation of TLRs in cultured adipocytes.
Involvement of TLRs in the development of inflam
mation in adipose tissue is also supported by a signifi
cant decrease of MCP1 and NFB in nuclear
extracts obtained from adipose tissue of TLR4defi
cient mice. These results suggest that TLR4 inhibition
may suppress the development of inflammation in
T2DM patients (Fig. 2).
It is possible that FFA may be the major mediators
of inflammation and IR. Activating TLR4 in skeletal
muscle cells, FFA thus stimulate activity of JNK and
IKKkinases. IKK prevents inhibition of B (I B );
this results in migration of NFB into the cell
nucleus, where it induces transcription of gene encod
ing proinflammatory cytokines (TNF, IL1, and
IL6) and their increased secretion by macrophages
[31, 32, 44, 45]. In turn, TNF, acting via p55 and
p75 TNFreceptors can induce formation of the
nuclear factor NFB and activation of stressinduced
kinases JNK, p38 and ERK 1/2 (extracellular stress
regulated kinases 1/2) in adipocytes [46]. Experimen
tal hypoxia caused activation of the transcription fac
tor NFB and the TNF gene promoter in fibro
blasts and adipocytes [47].
JNKkinase activates signaling STAT (Signal
Transducer and Activator of Transcription) proteins,
which mediate realization of various biological effects,
including the expression of genes associated with
inflammation, apoptosis, differentiation, growth,
morphogenesis, migration, and proliferation of cells
[48] (Fig. 2). At the same time, JNK and IKK are
mediators of FFAinduced IR. It was found, that these
kinases phosphorylate IRS1 serine residues; this
blocks insulin receptormediated phosphorylation of
IRS1 tyrosine residues. Moreover, phosphorylation
at serine /threonine residues enhances degradation of
IRS1. Thus, all these kinase effects contribute to the
formation of IR.
Besides FFA, a systemic inflammatory response
may be induced by chronic hyperglycemia (CHG)
[35, 49]. CHG mediates nonenzymatic glycation of
proteins and lipids resulted in the formation of
advanced glycation end products (AGEs), which in

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Lipolysis

TNF, IL1,
IL6

Pathogenassociated
molecular patterns

Cytokine
receptors

Saturated fatty acids

Tolllike receptors (2 and 4)

Ceramides and
other lipid
mediators

TAKKinase

JNKKinase

IKKKinase

Functions and
biogenesis of mitochondria

P38 MAPK
ROS

NFB STAT

EPR
stress

Damage
associated
molecular
patterns

AP1
Inflammasome

Proinflammatory cytokines and chemokines

Suppressor of cytokine
activated signal pathway

Recruitment and
activation of immune
cells (lymphocytes,
macrophages, and
granulocytes)

Hypoxia,
cytokine,
ROS

HIF1

Impairment of insulin signaling pathway

Fig. 2. The activation pathway of inflammation in obesity and interaction of this pathway with the insulin signaling cascade. Var
ious signaling molecules directly act at membrane (Tolllike receptors and cytokine receptors) and intracellular proteins, and also
indirectly, by interaction with effectors located on the surface of cell organelles (e.g. mitochondria, and EPR); this results in acti
vation of the inflammatory pathway. Transcription factors such as nuclear factor B (NFB), activation protein1 (AP1), signal
transducers and activators of transcription (STAT) activate subsequent cascades in this signaling path and this leads to the expres
sion of proteins inhibiting the insulin signaling pathway and induce proinflammation by activating immune cells. TNF
tumor necrosis factor; IL1, IL6interleukins 1 and 6; TAKkinasetransforming growth factor (TGFbeta)activated
kinase; HIF1hypoxiainducible factor 1; IKKinhibitor of kappa B kinase ; STATsignal transducer and activator of
transcription; P38 MAPKp38 mitogenactivated protein kinases; NFBnuclear factor kappa B), JNKcJunNH2 ter
minal kinase (adapted from [1]).

turn activate the receptor of advanced glycosylation

end products (RAGE). These receptors are expressed
by different types of cells including as smooth muscle
cells, Tcells, macrophages, podocytes, cardiomyo
cytes, and neurons [50]. Activating transcription fac
tor NFB and stress kinases ERK1 and ERK2, RAGE
cause the formation of ROS [35, 50].
In addition to this mechanism, ROS are formed in
reactions of glucose oxidation [51] and, together with
FFA ROS can activate the NLRP3 inflammasome
(cryopyrin, CIAS1, CLR1.1 (Caterpiller protein 1.1),
NALP3, PYPAF1), responsible for the activation of
caspase1; this results in the release of the active IL1
followed by subsequent production of IL1dependent
mediators [35, 52].
Numerous data have been accumulated on the
involvement of proinflammatory mediators TNF,
IL1, IL6, resistin, ROS and RNS (active nitrogen
forms) in the development of IR [31]. In obesity and
T2DM increased levels of TNF and IL6, produced

by adipocytes and adipose tissue macrophages activate

intracellular serine kinase [30, 40], which catalyzes the
phosphorylation of a serine residue in the IRS1 mol
ecule, and prevents normal phosphorylation
of tyrosine residues of both the insulin receptor and
IRS1. This results in impaired functioning of the
intracellular insulin signaling pathway and develop
ment of IR (Fig. 2).The link between serine phospho
rylation of IRS1 and IR development has been con
vincingly demonstrated by many studies [53, 54].
2.3. The Pathogenesis of the Inflammatory Response
in Obesity
Despite some advances in the study of the patho
genesis of the inflammatory response in obesity, the
initial pathogenetic factors triggering development of
inflammation in the adipose tissue are not fully under
stood. To date, the pathogenesis of IR associated with
obesity may be considered follows. In hypertrophic

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adipocytes active lipolysis occurs. Resultant FFA

interact with TLR4 and thus induce expression of
chemokines, which cause accumulation and activa
tion of macrophages in the adipose tissue [30, 55, 56].
In obesity, activated M1 macrophages (classically
activated) stimulate leukocyte infiltration, with
increased Th1, Th17 and CD8+Tcells and
decreased M2 macrophages (alternatively activated),
Treg, and Th2 cells in adipose tissue [5760]. Taking
into consideration that macrophages promote adipo
cyte hypertrophy it is clear that vicious circle of posi
tive feedback takes place in obesity: hypertrophied
adipocytes produce chemokines and their receptors
that initiate the recruitment of monocytes/macroph
ages to the adipose tissue. They promote subsequent
hypertrophy of adipocytes; some of which die produc
ing DAMPS, and also adhesion proteins and FFA; this
contributes to further prolongation of the inflamma
tory response [54].
Adiponectin directly promotes differentiation of
macrophages in the antiinflammatory phenotype
M2; acting on AdipoR1 via the AdipoR1 IL10
HO1dependent pathway it reduces the expression of
TLR4, while acting at AdipoR2 via the AdipoR2
IL4 STAT6dependent signaling pathway it
reduces production of proinflammatory cytokines
[61]. A strong correlation was found between mRNA
expression of genes encoding adiponectin and IB
(inhibiting the transcriptional activity of NFB).
High expression of IB, induced by adiponectin
suppresses proinflammatory activity of adipocytes
[38, 62].
Results of our studies demonstrating increased lev
els of proinflammatory cytokines (IL6, IFN, and
TGF) in patients with metabolic obesity and a
simultaneous decrease in blood major subpopulations
of Tlymphocytes and the increased level of activated
T(CD25+) and B(CD23+) lymphocytes and
monocytes (CD14+) [54] are also consistent with the
systemic nature of subclinical inflammation in MS.
We have found that mononuclear leukocytes derived
from peripheral blood of MS patients (BMI >
35.6 kg/m2) were characterized by enhanced ability to
spontaneously produce proinflammatory cytokines, at
relatively low degree of their mitogeninduced secre
tion [31, 64]. These changes may indicate a decrease in
the reserve capacity of mononuclear cells to synthesize
inflammatory mediators in conditions of prolonged
activation of intracellular metabolism caused by
chronic hyperinsulinemia, dyslipidemia, and their
antigenic stimulation by modified lipoproteins. In
addition, a significant decrease in quantitative charac
teristics of Tcells in MS [63], suggests functional
incompetence of mononuclear cells, which is also
confirmed by a reduced ability of mononuclear cells
from MS patients to secrete IL2 [64].
Thus, the data available in the literature and our
results suggest changes of the functional activity of

197

mononuclear cells under conditions of chronic

inflammation in MS; this can serve as a basis for the
development of pathogenetic approaches correcting
the balance of pro and antiinflammatory mediators
in MS, particularly in obesity. Their realization will
help to restore insulin sensitivity in MS.
2.4. Search Target for Treating Inflammation
and Adipose Tissue Insulin Resistance
To validate these hypotheses it is necessary to
obtain their clinical or experimental validation. In this
context, special attention should be paid to results of
clinical studies in which immunotherapy of T2DM
patients was targeted to neutralization of the proin
flammatory cytokines TNF and IL1 by mono
clonal antibodies. Use of antiTNF antibodies led
to disappointing results, as neutralization of TNF
did not normalize insulin sensitivity [65]. On the other
hand, in patients with severe inflammatory diseases
such as rheumatoid arthritis and Bekhterevs disease,
antiTNF therapy was successful because it caused
reduction of IR and other components of MS [66
68]. The potential effect of blockade of IL1 on insu
lin sensitivity is currently investigated. Effectiveness of
longterm antiIL1 therapy is being studied in a
clinical trial known as CANTOS [69]. This study
includes 17200 patients; during 4 years every three
months they will receive various doses of antiIL1
antibody. It is suggested that such longterm clinical
trials will culminate in a new cytokine therapy for the
prevention of diabetes, as well as to prove the autoin
flammatory nature of metabolic disorders.
JNKkinase is another potential molecular target
for the treatment of inflammatory diseases. As it was
already mentioned above, JNK influences both for
mation of IR and the development of inflammation.
However, choice of pharmacologically potent and
selective small molecule inhibitors of JNK is currently
limited. Compound A developed by Pfizer (Germany)
is an aminopyridine JNK inhibitor, which competes
with ATP. In obese mice this compound caused a
decrease in body weight, blood glucose, and triglycer
ide levels and also restored sensitivity to insulin [70]. A
single dose administration of BI78D3, another com
petitive inhibitor of JNK, restored insulin sensitivity in
T2DM mice [71]. Compound 19 is a powerful selec
tive competitive inhibitor of the latest generation of
JNK inhibitors; it competes with both protein sub
strate and to ATP. Daily intraperitoneal administra
tion of compound 19 (25 mg/kg) to mice with
impaired glucose tolerance (NONcNZO10an
experimental model of obesity and T2DM) for 4 days
caused normalization of glucose levels without causing
hypoglycemia [72]. These results indicate that JNK
inhibition is an effective way of restoring insulin sensi
tivity. However, a final assessment of the effectiveness
of JNK inhibition JNK needs longterm clinical trials.

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Evidence for the key role of cytokines in the patho

genesis of IR was obtained during clinical trials of
some antiinflammatory drugs. Administration
diacerein used for treatment of joint diseases
decreased plasma levels of TNF and IL1; however,
mechanisms of this effect remain unknown [72].
The antiinflammatory effect has been described for
AC201, which suppresses production of IL1.
Administration of AC201 to T2DM patients
decreased blood glucose levels [35]. Currently, these
studies should be cautiously interpreted due to the
limited information on application of this drug.
Results of clinical observations suggest that the
serum levels of proinflammatory cytokines TNF,
IL6 and/or CRP decreased in patients with hyperten
sion and T2DM during therapy with angiotensin
receptor blockers [73]. Interestingly, angiotensin II
receptor type1 are expressed on certain immune
competent cells (Tcells, monocytes, macrophages)
[35]. The experiment has shown that telmisartan, an
angiotensin II receptor antagonist, causes differentia
tion of adipose tissue macrophages with the anti
inflammatory M2 phenotype [74]. These data were
confirmed in clinical trials, in which angiotensin
receptor blockers and ACE (angiotensin concerting
enzyme) inhibitors not only decreased blood pressure
in T2DM patients, but also increased sensitivity of
adipose and muscle tissues to insulin [75].
3. NEW LINKS IN REALIZATION OF INSULIN
SIGNAL TRANSDUCTION
3.1. GPCRs, GRKs, Arrestins
Relatively recently new Gproteincoupled recep
tors (GPCRs) that regulate insulin secretion and tissue
sensitivity to this hormone have been described. Real
ization of GPCRs signaling requires G proteincou
pled receptor kinases (GRKs) and cytoplasmic pro
teins arrestins. For some GPCRs [18, 76] FFA and so
called FasGPCRs may act as physiological ligands.
Studies have shown that FasGPCRs influence secre
tion of insulin, glucagon, and incretins. After binding
of the ligand to its receptor GRKs phosphorylate
GPCR, which then interacts with the arrestins. Under
physiological conditions GRK2 suppresses the insulin
signal. In vitro experiments with cultured human adi
pocytes demonstrated a 2fold increase of GRK2
under conditions of IR [77]. Since GRKs regulate
insulindependent signaling pathways, they can be
regarded as a potential therapeutic target for IR cor
rection.
Arrestins can inhibit activation of NFB and
block transcription of proinflammatory cytokine
genes [32]. In addition to the antiinflammatory
effect, arrestin may influence cell sensitivity to insu
lin. In mouse experimental models and in patients
with IR, the level of arrestin 2 decreased [78].

Results of recent studies [48, 79] indicate that

arrestin1 mediates the effect glucagonlike pep
tide1 (GLP1) on pancreatic cells of the pancreas.
For example, an association between the GLP1R and
betaarrestin1 stimulated cAMP formation and insu
lin secretion by cells [80, 81].
FasGPCRs include GPRs 40, 41, 43, 84, 119, and
120 and have specific ligands and tissue distribution
[83]. It has been demonstrated that their activation (at
least, GPR40 and GPR119) directly stimulates insulin
secretion by cells and protects these cells against
glucose and lipotoxicity thus demonstrating their
important role in carbohydrate metabolism [83, 84].
Activation of FasGPCRs stimulates the production
of intestinal hormones GLP1 and glucosedependent
insulinotropic polypeptide (GIP), regulating insulin
secretion and feeding behavior [85, 86]. In addition to
these effects, certain FasGPCRs (GPR43, 84, and
120) modulate the inflammatory response of the cells
[82]. In particular, activation of GPR120 and arres
tin by docosahexaenoic and linolenic acids
decreased production of TNF, IL6 and MCP1
[87]. Thus, the facts discussed here emphasize the
importance of FasGPCR receptors in realization of
interconnected glucose homeostasis and proinflam
matory activity of cells.
3.2. Histone Deacetylase (HDAC)
Histone deacetylases, (HDACs) are a family of
enzymes; together with histone acetyltransferase
(HATs) they regulate acetylation of proteins. Inhibi
tion of HDAC activity increases acetylation of his
tones and nonhistone proteins, including NFB,
MyoD, p53, and nuclear factor of activated Tcells
(NFAT) [88]; this influences functional activity of
cells (their proliferation, differentiation, and apopto
sis) [89]. Relatively recently, some interesting data
have been obtained on the effects of HDAC on the
sensitivity of cells to insulin. It was found that histone
hyperacetylation induced by administration of a spe
cific HDAC inhibitor (ITF2357) increased insulin
production, protected pancreatic cells against
cytokineinduced apoptosis [90] and also reduced
production of nitric oxide (NO) and chemokines [91].
Experiment on HDAC6 knockout mice character
ized by chronic corticoid production did not reveal
development of hyperglycemia [92].
3.3. Peroxisome ProliferatorActivated Receptors
(PPAR)
Peroxisome proliferatoractivated receptor gamma
(PPAR) are nuclear receptors that function as tran
scription factors during activation of transcription and
expression of adipokine genes. There are two isoforms
of PPAR: PPAR1 and PPAR2. PPAR1 is
expressed by all cells of the body, whereas PPAR2 is
predominantly expressed by adipocytes. Binding of

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PATHOGENESIS OF INSULIN RESISTANCE IN METABOLIC OBESITY

PPAR ligands to the receptor, stimulates expression

of genes that regulate differentiation of preadipocytes
into mature adipocytes [93].
Recently it has been suggested that PPAR is a key
regulator of inflammatory and immune reactions
in adipose tissue [93]. For example, activation of
PPAR enhances insulin sensitivity in adipose and
muscle tissues due to suppression of the inflammatory
response [93, 94]. The expression of PPAR leads to
the formation of M2 macrophages [95] and inhibition
of TLR and IFNdependent inflammatory reac
tions. Cipolletta et al. [96 ] showed that the PPAR,
interacting with Foxp3, is involved in the accumula
tion and activation of Treg in adipose tissue.
Adipocytes are the major target cells for the PPAR
agonists. This class of compounds includes such phar
macological agents as pioglitazone and rosiglitazone,
which are widely used for therapy of T2DM patients
[97].
3.4. Fatty Acid Metabolites
Resolvins are new mediators derived from docosa
hexaenoic (DHA, C22: 6n3) and eicosapentaenoic
(EPA, C20: 5n3) fatty acids [98]. Along with leukot
rienes (LT) and prostaglandins (PG) resolvins exhibit
potent antiinflammatory and immunoregulatory
effects. They reduce the exudation in rats with experi
mental peritonitis [99] and possess immunoregulatory
[98] and neuroprotective activity [100]. It has been
established that micromolar concentrations of DHA
and nanomolar concentrations of resolvin D1 inhibit
activity of M1macrophages and increase the number
of M2cells in adipose tissue [101]. Besides the anti
inflammatory action, FFA may prevent the develop
ment of IR. Experimental studies have shown that
feeding obese animals with omega3 fatty acids pro
moted biosynthesis resolvin and they did not develop
diabetes and IR [102, 103]. Horrillo et al. [104] dem
onstrated that adipose tissue contains all the enzymes
necessary for formation of biologically active lipid
mediators derived from omega6 and omega3 poly
unsaturated essential fatty acids. Feeding of OB/OB
mice with DHA, significantly increased adiponectin
levels in adipose tissue and development of hepatic
steatosis and IR was not observed [102]. It is suggested
[105] that endogenous resolvin D1 will allow to
develop a new strategy for the treatment of obesity and
diabetes. The authors note that in leptindeficient
mice resolvin prevents accumulation of macrophages
in adipose tissue and restores insulin sensitivity.
3.5. MicroRNAs
MicroRNAs (miRNAs or miRs) are short non
coding RNAs, which regulate cellular transcriptome
and proteome [106]. There is experimental evidence
that miRNAs are involved in the regulation of metab
olism, cell proliferation, and apoptosis [107].

199

MicroRNAs represent a new class of carbohydrate

metabolism regulators that can improve insulin sensi
tivity in peripheral tissues.
Recently, the relationship between certain types
of microRNAs and development of IR has been rec
ognized [108]; this suggests a possible influence of
miRNAs on the development of T2DM. For example,
overexpression of microRNALet7 in mice resulted
in formation of IR and reduction of glucoseinduced
insulin secretion by the pancreas [109]. It was shown
that the microRNA107 can regulate the inflamma
tory process in the adipose tissue [110]. The TLR4 of
activated macrophages inhibited production of
microRNA107, which finally limits the proinflam
matory response and improves cell sensitivity to insu
lin [111].
CONCLUSIONS
Thus, identification of new biomarkers involved in
pathogenesis of chronic inflammation of adipose tis
sue and insulin resistance, together with the final spec
ification of the mechanisms of energy homeostasis dis
orders are needed to develop new methods (based on
the physiological characteristics of adipose tissue
metabolism) for prevention or treatment of metabolic
syndrome.
ACKNOWLEDGMENTS
The study was performed within the framework of
the Federal Target Program Scientific and Scientific
Pedagogical Personnel of Innovative Russia for
20092013 years (State contract no. P329, and under
the agreement no. 14.A18.21.1518).
REFERENCES
1. Hirabara, S.M., Gorjo, R., Vinolo, M.A., Rod
rigues, A.C., Nachbar, R.T., and Curi R., J. Biomed.
Biotechnol., 2012, vol. 2012, ID 379024.
2. Tronko, N.D., Kovzun, E.I., and Pushkarev, V.M.,
Zhurn. Ukr. Nat. Akad. Med. Nauk, 2012, vol. 18,
no. 4, pp. 430439.
3. Burks, D.J. and White, M.F., Diabetes, 2001, vol. 50,
pp. 140145.
4. Durmu s Tekir, S., mit P., Toku, E.A., and
lgen, K.O., J. Biomed. Biotechnol., 2010, vol. 2010,
ID 690925.
5. Thirone, A.C., Huang, C., and Klip, A., Trends Endo
crinol. Metab., 2006, vol. 17, pp. 7278.
6. Thong, F.S.L., Dugani, C.B., and Klip, A., Physiology,
2005, vol. 4, pp. 271284.
7. Sharma, M.D., Garber, A.J., and Farmer, J.A.,
Endocr. Pract., 2008, vol. 14, pp. 373380.
8. Mitra, P., Zheng, X., and Czech, M.P., J. Biol. Chem.,
2004, vol. 279, pp. 3743137435.
9. Chang, L., Chiang, S., and Saltiel, A.R., Mol. Med.,
2004, vol. 10, nos. 712, pp. 6571.

BIOCHEMISTRY (MOSCOW) SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY

Vol. 8

No. 3

2014

200

LITVINOVA et al.

10. Skolnik, E.Y., Batzer, A., Li, N., Lee, C.H., Lowen
stein, E., Mohammadi, M., Margolis, B., and
Schlessinger, J., Science, 1993, vol. 260, no. 5116,
pp. 19531955.
11. Gureasko, J., Galush, W.J., Boykevisch, S., Sonder
mann, H., BarSagi, D., Groves, J.T., and Kuriyan, J.,
Nat. Struct. Mol. Biol., 2008, vol. 15, pp. 452461.
12. CombettesSouverain, M. and Issad, T., Diabetes
Metab., 1998, vol. 24, pp. 477489.
13. Somwar, R., Kim, D.Y., Sweeney, G., Huang, C.,
Niu, W., Lador, C., Ramlal, T., and Klip, A., Biochem. J.,
2001, vol. 359, pp. 639649.
14. Rains, J.L. and Jain, S.K., Free Radic. Biol. Med.,
2011, vol. 50, pp. 567575.
15. Henriksen, E.J., DiamondStanic, M.K., and Mar
chionne, E.M., Free Radic. Biol. Med., 2011, vol. 51,
pp. 993999.
16. KontrogianniKonstantopoulos, A., Benian, G., and
Granzier, H., J. Biomed. Biotechnol., 2012, vol. 2012,
ID 930836.
17. Martins, A.R., Nachbar, R.T., Gorjao, R., Vinolo, M.A.,
Festuccia, W.T., Lambertucci, R.H., CuryBoaven
tura, M.F., Silveira, L.R., Curi, R., and Hirabara, S.M.,
Lipids Health Dis., 2012, vol. 11, p. 30.
18. Newsholme, P., Haber, E.P., Hirabara, S.M.,
Rebelato, E.L., Procopio, J., Morgan, D., Oliveira
Emilio, H.C., Carpinelli, A.R., and Curi, R., J. Physiol.,
2007, vol. 583, pp. 924.
19. Brehm, A., Krssak, M., Schmid, A.I., Nowotny, P.,
Waldhusl, W., and Roden, M., Diabetes, 2006,
vol. 55, pp. 136140.
20. Lenoir, O., Flosseau, K., Ma, F.X., Blondeau, B.,
Mai, A., BasselDuby, R., Ravassard, P., Olson, E.N.,
Haumaitre, C., and Scharfmann, R., Diabetes, 2011,
vol. 60, pp. 28612871.
21. Rajendran, R., Garva, R., KrsticDemonacos, M.,
and Demonacos, C., J. Biomed. Biotechnol., 2011,
vol. 2011, ID 368276.
22. Bashan, N., Kovsan, J., Kachko, I., Ovadia, H., and
Rudich, A., Physiol. Rev., 2009, vol. 89, pp. 2771.
23. Zhang, L., Haraguchi, S., Koda, T., Hashimoto, K,
and Nakagawara, A., J. Biomed. Biotechnol., 2011,
vol. 2011, ID 831092.
24. Pankratova, M.A., Pirozhkov, S.V., Balabolkin, M.I.,
and Levitzkii, P.F., Sakharnyi Diabet, 2006, no. 2,
pp. 1215.
25. Laybutt, D.R., Kaneto, H., Hasenkamp, W., Grey, S.,
Jonas, J.C., Sgroi, D.C., Groff, A., Ferran, C., Bon
nerWeir, S., Sharma, A., and Weir, G.C., Diabetes,
2002, vol. 51, pp. 413423.
26. Schwartz, V., Ter. Arkhiv, 2009, no. 10, pp. 7480.
27. FernandezReal, J.M. and Ricart, W., Endocr. Rev.,
2004, vol. 24, pp. 278301.
28. Schwartz, V., Kardiologiya, 2009, no. 12, pp. 8086.
29. Medzhitov, R., Nature, 2008, vol. 454, no. 7203,
pp. 428435.
30. Mathis, D., Cell. Metab., 2013, vol. 17, pp. 851859.
31. Kulikov, D.I., Vasilenko, M.A., Kirienkova, E.V.,
Mazunin, I.O., Zatolokin, P.A., and Litvinova, L.S.,
Kant Baltic Federal University Vestnik, 2013, vol. 4,
pp. 5156.

32. Hotamisligil, G.S., Nature, 2006, vol. 444, no. 7121,

pp. 860867.
33. Fuentes, E., Fuentes, F., Vilahur, G., Badimon, L.,
and Palomo, I., Mediators Inflamm., 2013, vol. 2013,
ID 136584.
34. Ellingsgaard, H., Hauselmann, I., Schuler, B.,
Habib, A.M., Baggio, L.L., Meier, D.T., Eppler, E.,
Bouzakri, K., Wueest, S., Muller, Y.D.,
Hansen, A.M., Reinecke, M., Konrad, D., Gas
smann, M., Reimann, F., Halban, P.A., Gromada, J.,
Drucker, D.J., Gribble, F.M., Ehses, J.A., and
Donath, M.Y., Nat. Med., 2011, vol. 17, pp. 1481
1489.
35. Donath, M.Y., Dalmas, ., Sauter, N.S., Bni
Schnetzler, M., Cell Metab., 2013, vol. 17, pp. 860
872.
36. Turu, M.M., Slevin, M., Matou, S., West, D.,
Rodrguez, C., Luque, A., GrauOlivares, M., Badi
mon, L., MartinezGonzalez, J., and Krupinski, J.,
BMC Cell. Biol., 2008, vol. 9, p. 47.
37. Kirienkova, E.V., Litvinova, L.S., Seledtsov, V.I.,
Zatolokin, P.A., and Aksenova, N.N., Klin. Labor.
Diagn., 2012, no. 12, pp. 35.
38. Litvinova, L.S., Zatolokin, P.A., Poznyak, E.V.,
Seledtsova, I.A., Kirienkova, E.V., and Seledtsova, V.I.,
Annaly Khirurgii, prilozhenie 1, 2011, pp. 3940.
39. Sun, K., Kusminski, C.M., and Scherer, P.E., J. Clin.
Invest., 2011, vol. 121, no. 6, pp. 20942101.
40. Aderem, A. and Ulevitch, R.J., Nature, 2000, vol. 406,
no. 6797, pp. 782787.
41. Dasu, M.R., Devaraj, S., Park, S., and Jialal, I., Dia
betes Care, 2010, vol. 33, no. 4, pp. 861868.
42. Kim, H.S., Han, M.S., Chung, K.W., Kim, S.,
Kim, E., Kim, M.J., Jang, E., Lee, H.A., Youn, J.,
Akira, S., and Lee, M.S., Immunity, 2007, vol. 27,
no. 2, pp. 321333.
43. Kopp, A., Buechler, C., Bala, M., Neumeier, M.,
Schlmerich, J., and Schffler, A., Endocrinology,
2010, vol. 151, pp. 10971108.
44. Haversen, L., Danielsson, K.N., Fogelstrand, L., and
Wiklund, O., Atherosclerosis, 2009, vol. 202, pp. 382
393.
45. Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L.,
Huang, M.T., Brickey, W.J. and Ting, J.P., Nat. Immu
nol., 2011, vol. 12, pp. 408415.
46. Rydn, M., Dicker, A., Van Harmelen, V., Hauner, H.,
Brunnberg, M., Perbeck, L., Lonnqvist, F., and
Arner, P., J. Biol. Chem., 2002, vol. 277, pp. 1085
1091.
47. Ye, J., Gao, Z., Yin, J., and He, Q., Am. J. Physiol.
Endocrinol. Metab., 2007, vol. 293, pp. 11181128.
48. Davis, H.M., Carpenter, D.C., Stahl, J.M.,
Zhang, W., Hynicka, W.P., and Griswold, D.E.,
J. Immunol. Methods, 2000, vol. 240, pp. 125132.
49. Deopurkar, R., Ghanim, H., Friedman, J., Abuay
sheh, S., Sia, C.L., Mohanty, P., Viswanathan, P.,
Chaudhuri, A., and Dandona, P., Diabetes Care, 2010,
vol. 33, no. 5, pp. 991997.
50. Yan, S.F., Ramasamy, R., and Schmidt, A.M., J. Mol.
Med. (Berl.), 2009, vol. 87, no. 3, pp. 235247.

BIOCHEMISTRY (MOSCOW) SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY

Vol. 8

No. 3

2014

PATHOGENESIS OF INSULIN RESISTANCE IN METABOLIC OBESITY

51. Zhou, R., Tardivel, A., Thorens, B., Choi, I., and
Tschopp, J., Nat. Immunol., 2010, vol. 11, pp. 136
140.
52. BniSchnetzler, M., Boller, S., Debray, S.,
Bouzakri, K., Meier, D.T., Prazak, R., KerrConte, J.,
Pattou, F., Ehses, J.A., Schuit, F.C., and
Donath, M.Y., Endocrinology, 2009, vol. 150,
pp. 52185229.
53. Peppa, M., Koliaki, C., Nikolopoulos, P.,
ad Raptis, S.A., J. Biomed. Biotechnol., 2010,
vol. 2010, ID 527850.
54. Schwartz, V., Probl. Endokrinol., 2009, vol. 55, no. 1,
pp. 3844.
55. MotheSatney, I., Filloux, C., Amghar, H., Pons, C.,
Bourlier, V., Galitzky, J., Grimaldi, P.A., Fral, C.C.,
Bouloumi, A., Van Obberghen, E., and Neels, J.G.,
Diabetes, 2012, vol. 61, no. 9, pp. 23112319.
56. Kurokaw, J., Nagano, H., Ohara, O., Kubota, N.,
Kadowaki, T., Arai, S., and Miyazaki, T., Proc. Natl.
Acad. Sci. USA, 2011, vol. 108, pp. 1207212077.
57. Yang, H., Youm, Y.H., Vandanmagsar, B., Ravus
sin, A., Gimble, J.M., Greenway, F., Stephens, J.M.,
Mynatt, R.L., and Dixit, V.D., J. Immunol., 2010,
vol. 185, pp. 18361845.
58. Feuerer, M., Herrero, L., Cipolletta, D., Naaz, A.,
Wong, J., Nayer, A., Lee, J., Goldfine, A.B.,
Benoist, C., Shoelson, S., and Mathis, D., Nat. Med.,
2009, vol. 15, pp. 930939.
59. Rocha, V.Z., Folco, E.J., Sukhova, G., Shimizu, K.,
Gotsman, I., Vernon, A.H., and Libby, P., Circ. Res.,
2008, vol. 103, pp. 467476.
60. Bertola, A., Ciucci, T., Rousseau, D., Bourlier, V.,
Duffaut, C., Bonnafous, S., BlinWakkach, C., Rod
olphe, A.A., Gugenheim, I.J., Tran, A.B., and
Wakkach, P.G., Diabetes, 2012, vol. 61, pp. 2238
2247.
61. Mandal, P., Pratt, B.T., Barnes, M., McMullen, M.R.,
and Nagy, L.E., J. Biol. Chem., 2011, vol. 286,
pp. 1346013469.
62. Zamboni, M., Di Francesco, V., Garbin, U., Fratta
Pasini, A., Mazzali, G., Stranieri, C., Zoico, E., Fan
tin, F., Bosello, O., and Cominacini, L., Int. J. Obes.
(Lond.), 2007, vol. 31, pp. 11041109.
63. Litvinova, L.S., Kirienkova, E.V., Aksenova, N.N.,
Zatolokin, P.A., and Gazatova, N.D., Byull. Sib.
GMU, 2012, vol. 3, pp. 5358.
64. Litvinova, L.S., Kirienkova, E.V., Gazatova, N.D.,
Zatolokin, P.A., Vasilenko, M.A., Simbirtsev, M.A.,
and Aksenova, N.N., Tsitokiny i Vospalenie, 2013,
vol. 12, no. 3, pp. 6267.
65. Ofei, F., Hurel, S., Newkirk, J., Sopwith, M., and Tay
lor, R., Diabetes, 1996, vol. 45, pp. 881885.
66. GonzalezGay, M.A., De Matias, J.M., Gonzalez
Juanatey, C., GarciaPorrua, C., SanchezAndrade, A.,
Martin, J., and Llorca, J., Clin. Exp. Rheumatol., 2006,
vol. 24, pp. 8386.
67. GonzalezGay, M.A., GonzalezJuanatey, C.,
VazquezRodriguez, T.R., MirandaFilloy, J.A., and
Llorca, J., Ann. NY Acad. Sci., 2010, vol. 1193,
pp. 153159.

201

68. Stagakis, I., Bertsias, G., Karvounaris, S., Kavousan

aki, M., Virla, D., Raptopoulou, A., Kardassis, D.,
Boumpas, D.T., and Sidiropoulos, P.I., Arthritis Res.
Ther., 2012, vol. 14, p. R 141.
69. Ridker, P.M., Thuren, T., Zalewski, A., and Libby, P.,
Am. Heart J., 2011, vol. 162, no. 4, pp. 597605.
70. Cho, H., Black, S.C., Looper, D., Shi, M., KellySul
livan, D., Timofeevski, S., Siegel, K., Yu, X.H.,
McDonnell, S.R., Chen, P., Yie, J., Kathleen, M.O.,
Fraser, J., and Briscoe, C.P., Am. J. Physiol. Endo
crinol. Metab., 2008, vol. 295, pp. 11421151.
71. Stebbins, J.L., De, S.K., Machleidt, T., Becattini, B.,
Vazquez, J., Kuntzen, C., Chen, L.H., Cellitti, J.F.,
RielMehan, M., Emdadi, A., Solinas, G., Karin, M.,
and Pellecchia, M., Proc. Natl. Acad. Sci. USA, 2008,
vol. 105, pp. 1680916813.
72. RamosZavala, M.G., GonzlezOrtiz, M., Mar
tnezAbundis, E., RoblesCervantes, J.A., Gonzlez
Lpez, R., and SantiagoHernndez, N.J., Diabetes
Care, 2011, vol. 34, pp. 15911594.
73. Pavlatou, M.G., Mastorakos, G., Margeli, A., Kousk
ouni, E., Tentolouris, N., Katsilambros N.,
Chrousos, G.P., and Papassotiriou, I., Eur. J. Clin.
Invest., 2011, vol. 41, pp. 652658.
74. Fujisaka, S., Usui, I., Kanatani, Y., Ikutani, M.,
Takasaki, I., Tsuneyama, K., Tabuchi, Y., Bukhari, A.,
Yamazaki, Y., Suzuki, H., Senda, S., Aminuddin, A.,
Nagai, Y., Takatsu, K., Kobayashi, M., and Tobe, K.,
Endocrinology, 2011, vol. 152, pp.17891799.
75. Van der Zijl, N.J., Moors, C.C., Goossens, G.H.,
Blaak, E.E., and Diamant, M., Diabetes Obes. Metab.,
2012,vol. 14, p. 586595.
76. Yu, A.M., Expert Opin. Drug. Metab. Toxicol., 2009,
vol. 5, pp. 15131528.
77. GarciaGuerra, L., NietoVazquez, I., Vila
Bedmar, R., JuradoPueyo, M., Zalba, G., Dez, J.,
Murga, C., FernndezVeled, S., Mayor, F., Jr., and
Lorenzo, M., Diabetes, 2010, vol. 59, pp. 24072417.
78. Luan, B., Zhao, J., Wu, H., Duan, B., Shu, G.W.,
Wang, X.Y., Li, D., Jia, W., Kang, J., and Pei, G.,
Nature, 2009, vol. 457, pp. 11461150.
79. Hotamisligil,
G.S.,
Shargill,
N.S.,
and
Spiegelman, B.M., Science, 1993, vol. 259, vol. 5091,
pp. 8791.
80. Feng, X., Wang, W., Liu, J., and Liu, Y., Mol. Biol.
Rep., 2011, vol. 38, pp. 25172528.
81. Mayor, F., Jr., Lucas, E., JuradoPueyo, M., Garcia
Guerra, L., NietoVazquez, I., VilaBedmar, R.,
FernndezVeledo, S., and Murga, C., Arch. Physiol.
Biochem., 2011, vol. 117, pp. 125130.
82. Vinolo, M.A., Hirabara, S.M., and Curi, R., Curr.
Opin. Clin. Nutr. Metab. Care, 2012, vol. 15, pp. 112
116.
83. Tuo, Y., Feng, D.D., Wang, D.F., Sun, J., Li, S.B.,
and Chen, C., Clin. Exp. Pharmacol. Physiol., 2012,
vol. 39, pp. 423428.
84. Chu, Z.L., Jones, R.M., He, H., Carroll, C., Gutier
rez, V., Lucman, A., Moloney, M., Gao, H., Monda
la, H., Bagnol, D., Unett, D., Liang, Y., De
marest, K., Semple, G., Behan, D.P., and Leonard, J.,
Endocrinology, 2007, vol. 148, pp. 26012609.

BIOCHEMISTRY (MOSCOW) SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY

Vol. 8

No. 3

2014

202

LITVINOVA et al.

85. Edfalk, S., Steneberg, P., and Edlund, H., Diabetes,

2008, vol. 57, pp. 22802287.
86. Hansen, K.B., Rosenkilde, M.M., Knop, F.K., Well
ner, N., Diep, T.A., Rehfeld, J.F., Andersen, U.B.,
Holst, J.J., and Hansen, H.S., J. Clin. Endocrinol.
Metab., 2011, vol. 96, pp. 14091417.
87. Oh, D.Y., Talukdar, S., Bae, E.J., Imamura, T., Mori
naga, H., Fan, W., Li, P., Lu, W.J., Watkins, S.M., and
Olefsky, J.M., Cell, 2010, vol. 142, pp. 687698.
88. Glodak, M.A., Sengupta, N., Zhang, X., and Seto, E.,
Gene, 2005, vol. 363, pp. 1523.
89. Grabiec, A.M., Tak, P.P., and Reedquist, K.A., Crit.
Rev. Immunol., 2011, vol. 31, pp. 233263.
90. Christensen, D.P., Dahllf, M., Lundh, M., Rasmus
sen, D.N, Nielsen, M.D., Billestrup, N.,
Grunnet, L.G., and MandrupPoulsen, T., Mol. Med.,
2011, vol. 17, pp. 378390.
91. Lewis, E.C., Blaabjerg, L., Strling, J., Ronn, S.G.,
Mascagni, P., Dinarello, C.A., and Mandrup
Poulsen, T., Mol. Med., 2011, vol. 17, pp. 369377.
92. Winkler, R., Benz, V., Clemenz, M., Bloch, M.,
ForystLudwig, A., Wardat, S., Witte, N.,
Trappiel, M., Namsolleck, P., Mai, K., Spranger, J.,
Matthias, G., Roloff, T., Truee, O., Kappert, K.,
Schupp, M., Matthias, P., and Kintscher, U., Diabetes,
2012, vol. 61, 513523.
93. Fuentes, E., GuzmnJofre, L., MooreCarrasco, R.,
and Palomo, I., Mol. Med. Rep., 2013, vol. 8,
pp. 16111616.
94. Chiarelli, F. and Di Marzio, D., Vasc. Health Risk.
Manag., 2008, vol. 4, pp. 297304.
95. Odegaard,
J.I.,
RicardoGonzalez,
R.R.,
Goforth, M.H., Morel, C.R., Subramanian, V.,
Mukundan, L., Red Eagle, A., Vats, D.,
Brombacher, F., Ferrante, A.W., and Chawla, A.,
Nature, 2007, vol. 447, no. 7148, pp. 11161120.
96. Cipolletta, D., Feuerer, M., Li, A., Kamei, N., Lee, J.,
Shoelson, S.E., Benoist, C., and Mathis, D., Nature,
2012, vol. 486, no. 7404, pp. 549553.
97. Sugii, S. and Evans, R.M., FEBS Letts., 2011, vol. 585,
no. 13, pp. 21212128.

98. Serhan, C.N., Hong, S., Gronert, K., Colgan, S.P.,

Devchand, P.R., Mirick, G., and Moussignac, R.L.,
J. Exp. Med., 2002, vol. 196, pp. 10251037.
99. Clish, C.B., OBrien, J.A., Gronert, K., Stahl, G.L.,
Petasis, N.A., and Serhan, C.N., Proc. Natl. Acad. Sci.
USA, 1999, vol. 96, pp. 82478252.
100. Mukherjee, P.K., Marcheselli, V.L., Barreiro, S.,
Hu, J., Bok, D., and Bazan, N.G., Proc. Natl. Acad.
Sci. USA, 2007, vol. 104, pp. 1315213157.
101. Titos, E., Rius, B., GonzlezPriz, A., Lpez
Vicario, C., MornSalvador, E., Martnez
Clemente, M., Arroyo, V., and Clria, J., J. Immunol.,
2011, vol. 187, pp. 54085418.
102. GonzlezPriz, A., Horrillo, R., Ferr, N., Gro
nert, K., Dong, B., MornSalvador, E., Titos, E.,
MartnezClemente,
M.,
LpezParra,
M.,
Arroyo, V., and Clria, J., FASEB J., 2009, vol. 23,
pp. 19461957.
103. White, P.J., Arita, M., Taguchi, R., Kang, J.X., and
Marette, A., Diabetes, 2010, vol. 59, pp. 30663073.
104. Horrillo, R., GonzlezPriz, A., MartnezClem
ente, M., LpezParra, M., Ferr, N., Titos, E.,
MornSalvador, E., Deulofeu, R., Arroyo, V., and
Clria, J., J. Immunol., 2010, vol. 184, pp. 39783987.
105. Hellmann, J., Tang, Y., Kosuri, M., Bhatnagar, A., and
Spite, M., FASEB J., 2011, vol. 25, pp. 23992407.
106. Yu, C., Chen, Y., Cline, G.W., Zhang, D., Zong, H.,
Wang, Y., Bergeron, R., Kim, J.K., Cushman, S.W.,
Cooney, G.J., Atcheson, B., White, M.F.,
Kraegen, E.W., and Shulman, G.I., J. Biol. Chem.,
2002, vol. 277, pp. 5023050236.
107. Underbayev, C., Kasar, S., Yuan, Y., and Raveche, E.,
J. Biomed. Biotechnol., 2012, vol. 2012, ID 758169.
108. Xie, H., Lim, B., and Lodish, H.F., Diabetes, 2009,
vol. 58, pp. 10501057.
109. Frost, R.J.A. and Olson, E.N., Proc. Natl. Acad. Sci.
USA, 2011, vol. 108, pp. 2107521080.
110. Foley, N.H. and ONeill, L.A., J. Leukoc. Biol., 2012,
vol. 92, pp. 521527.
111. Hennessy, E.J., Sheedy, F.J., Santamaria, D., Barba
cid, M., and ONeill, A.J., J. Biol. Chem., 2011,
vol. 286, pp. 2553125539.
Translated by A. Medvedev

BIOCHEMISTRY (MOSCOW) SUPPLEMENT SERIES B: BIOMEDICAL CHEMISTRY

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2014