ISSN 19907508, Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2014, Vol. 8, No. 3, pp. 192–202. © 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: [email protected] Received May 6, 2013

Abstract—This 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 αsubunits and two transmembrane βsubunits. αSubunits have affinity for insulin, while βsubunits exhibit tyrosine kinase activity. Insulin binds to the αsubunit; this causes conformational changes and activation of βsubunit 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 [1–3, 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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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, TC10α and TC10β 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, GSK3β, 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 β (IKKβ) 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 α (TNFα), interleukin1β , and 6 (IL1β, 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 βcells of islets of Langerhans and consequently impaired insu lin secretion, may be associated with activation of hyperglycemiamediated oxidative stress [25]. The βcells 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 βcells, decreased IR, and improved glucose tolerance [26]. As mentioned previously, some of the serine/threo nine kinases (e.g. JNK, PKC, GSK3, NFκB, and p38), activated during oxidative stress, mediate expression of proinflammatory molecules such as TNFα, 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 (MAMPs—microbial associated molecular patterns), as well as by molecules which can initiate the formation of immune memory response to noninfectious inflammatory origin (DAMPS—dam 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 IκB

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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 (TNFα, IL1β, IL6, IL8, transforming growth fac tor (TGFβ), 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 αcells [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, TNFα, 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

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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 NFκB 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 κB (I κB α); this results in migration of NFκB into the cell nucleus, where it induces transcription of gene encod ing proinflammatory cytokines (TNFα, IL1β, and IL6) and their increased secretion by macrophages [31, 32, 44, 45]. In turn, TNFα, acting via p55 and p75 TNFreceptors can induce formation of the nuclear factor NFκB 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 NFκB and the TNFα 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 IKKβ 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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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 κB (NFκB), 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. TNFα— tumor necrosis factor; IL1β, IL6—interleukins 1β and 6; TAKkinase—transforming growth factor β (TGFbeta)activated kinase; HIF1—hypoxiainducible factor 1; IKKβ—inhibitor of kappa B kinase β; STAT—signal transducer and activator of transcription; P38 MAPK—p38 mitogenactivated protein kinases; NFκB—nuclear factor kappa B), JNK—cJunNH2 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 NFβB 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 IL1β followed by subsequent production of IL1dependent mediators [35, 52]. Numerous data have been accumulated on the involvement of proinflammatory mediators TNFα, IL1, IL6, resistin, ROS and RNS (active nitrogen forms) in the development of IR [31]. In obesity and T2DM increased levels of TNFα 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 [57–60]. 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 IκBα (inhibiting the transcriptional activity of NFκB). High expression of IκBα, induced by adiponectin suppresses proinflammatory activity of adipocytes [38, 62]. Results of our studies demonstrating increased lev els of proinflammatory cytokines (IL6, IFNγ, and TGFβ) 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

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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 TNFα and IL1β by mono clonal antibodies. Use of antiTNFα antibodies led to disappointing results, as neutralization of TNFα did not normalize insulin sensitivity [65]. On the other hand, in patients with severe inflammatory diseases such as rheumatoid arthritis and Bekhterev’s disease, antiTNFα therapy was successful because it caused reduction of IR and other components of MS [66– 68]. The potential effect of blockade of IL1β on insu lin sensitivity is currently investigated. Effectiveness of longterm antiIL1β 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 antiIL1β 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 (NONcNZO10—an 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 IL1β; however, mechanisms of this effect remain unknown [72]. The antiinflammatory effect has been described for AC201, which suppresses production of IL1β. 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 TNFα, 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. βArrestins can inhibit activation of NFκB and block transcription of proinflammatory cytokine genes [32]. In addition to the antiinflammatory effect, βarrestin may influence cell sensitivity to insu lin. In mouse experimental models and in patients with IR, the level of βarrestin 2 decreased [78].

Results of recent studies [48, 79] indicate that βarrestin1 mediates the effect glucagonlike pep tide1 (GLP1) on pancreatic βcells of the pancreas. For example, an association between the GLP1R and betaarrestin1 stimulated cAMP formation and insu lin secretion by βcells [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 βcells 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 βarres tin by docosahexaenoic and αlinolenic acids decreased production of TNFα, 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 NFκB, 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 βcells 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 (PPARγ) Peroxisome proliferatoractivated receptor gamma (PPARγ) are nuclear receptors that function as tran scription factors during activation of transcription and expression of adipokine genes. There are two isoforms of PPARγ: PPARγ1 and PPARγ2. PPARγ1 is expressed by all cells of the body, whereas PPARγ2 is predominantly expressed by adipocytes. Binding of

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PPARγ ligands to the receptor, stimulates expression of genes that regulate differentiation of preadipocytes into mature adipocytes [93]. Recently it has been suggested that PPARγ is a key regulator of inflammatory and immune reactions in adipose tissue [93]. For example, activation of PPARγ enhances insulin sensitivity in adipose and muscle tissues due to suppression of the inflammatory response [93, 94]. The expression of PPARγ leads to the formation of M2 macrophages [95] and inhibition of TLR and IFNγdependent inflammatory reac tions. Cipolletta et al. [96 ] showed that the PPARγ, interacting with Foxp3, is involved in the accumula tion and activation of Treg in adipose tissue. Adipocytes are the major target cells for the PPARγ 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].

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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 2009–2013 years (State contract no. P329, and under the agreement no. 14.A18.21.1518). REFERENCES 1. Hirabara, S.M., Gorjão, R., Vinolo, M.A., Rod rigues, A.C., Nachbar, R.T., and Curi R., J. Biomed. Biotechnol., 2012, vol. 2012, ID 379024. 2. Tron’ko, N.D., Kovzun, E.I., and Pushkarev, V.M., Zhurn. Ukr. Nat. Akad. Med. Nauk, 2012, vol. 18, no. 4, pp. 430–439. 3. Burks, D.J. and White, M.F., Diabetes, 2001, vol. 50, pp. 140–145. 4. Durmu s¸ Tekir, S., Ümit P., Toku, E.A., and Ülgen, 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. 72–78. 6. Thong, F.S.L., Dugani, C.B., and Klip, A., Physiology, 2005, vol. 4, pp. 271–284. 7. Sharma, M.D., Garber, A.J., and Farmer, J.A., Endocr. Pract., 2008, vol. 14, pp. 373–380. 8. Mitra, P., Zheng, X., and Czech, M.P., J. Biol. Chem., 2004, vol. 279, pp. 37431–37435. 9. Chang, L., Chiang, S., and Saltiel, A.R., Mol. Med., 2004, vol. 10, nos. 7–12, pp. 65–71.

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