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TRIENNIAL GROWTH SYMPOSIUM |
in myocytes and brown adipocytes1,2Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain
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Abstract |
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has been proposed as a link between obesity and insulin resistance because TNF- is overexpressed in adipose tissues of obese animals and humans, and obese mice lacking either TNF- or its receptor show protection against developing insulin resistance. Direct exposure to TNF- induces a state of insulin resistance in terms of glucose uptake in myocytes and brown adipocytes because of the activation of proinflammatory pathways that impair insulin signaling at the level of the insulin receptor substrate (IRS) proteins. In this regard, the Ser307 residue in IRS-1 has been identified as a site for the inhibitory effects of TNF- in myotubes, with p38 mitogen-activated protein kinase and inhibitor kB kinase being involved in the phosphorylation of this residue. Conversely, Ser phosphorylation of IRS-2 mediated by TNF- activation of mitogen-activated protein kinase was the mechanism found in brown adipocytes. Protein-Tyr phosphatase (PTP)1B acts as a physiological, negative regulator of insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in muscle and white adipose tissue of obese and diabetic humans and rodents. Moreover, up-regulation of PTP1B expression was recently found in cells treated with TNF- Accordingly, myocytes and primary brown adipocytes deficient in PTP1B are protected against insulin resistance induced by this cytokine. Furthermore, down-regulation of PTP1B activity is possible by the use of pharmacological agonists of nuclear receptors that restore insulin sensitivity in the presence of TNF-. In conclusion, the lack of PTP1B in muscle and brown adipocytes increases insulin sensitivity and glucose uptake and could confer protection against insulin resistance induced by adipokines.
Key Words: glucose uptake • liver X receptor • protein-tyr phosphatase 1B • obesity • p38 mitogen-activated protein kinase • rosiglitazone
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INTRODUCTION |
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). A number of signaling pathways can be activated downstream of IRS proteins. Molecules containing the Src homology 2 domain, including the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), Grb-2, and others, are recruited to the Tyr-phosphorylated IRS and transmit a cascade of signals, which consist of 2 major elements, that is, Ras/Raf/extracellular signal-regulated kinase (ERK) and PI3K/AKT (protein kinase B)/p70S6 (ribosomal p7056 kinase) kinase pathways (Virkamaki et al., 1999). A parallel mitogen-activated protein kinase (MAPK), p38MAPK, has been shown to be stimulated by insulin in several cell systems, including skeletal muscle (Cuenda and Rousseau, 2007). On the other hand, the insulin-signaling cascade is negatively regulated by protein phosphatases, including Tyr, Ser, and lipid phosphatases. Most notably, protein-Tyr phosphatase (PTP)1B acts by dephosphorylating the phosphotyrosine residues of the IR and IRS-1 (Goldstein et al., 2000). This review is focused on examining alterations in insulin-signaling pathways in states of insulin resistance associated with obesity. |
INSULIN ACTION ON GLUCOSE TRANSPORT |
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, 2002). Adipose tissues, including the most abundant white adipose tissue (WAT) and the thermogenic brown adipose tissue (BAT), are also under insulin control. In fetal brown adipocytes, insulin and IGF-I, acting independently and through the activation of the IRS-PI3K signaling pathway, up-regulated the expression of adipogenic-related genes at the transcriptional level (Teruel et al., 1996; Valverde et al., 2005). In addition to adipogenesis, insulin and IGF-I are thermogenic factors through their ability to increase the transcription rate of the uncoupling protein-1 gene (Lorenzo et al., 1993) by a mechanism dependent on activation of the PI3K and p21ras signaling cascades (Lorenzo et al., 1996; Teruel et al., 1998).
Glucose transport is the main metabolic aspect regulated by insulin in peripheral tissues and is maintained mainly by the activity of insulin-regulated glucose transporter (GLUT)4, although the ubiquitous GLUT1 glucose transporter also is often expressed at appreciable levels. In principle, there are at least 3 mechanisms by which insulin could modulate GLUT4 function to increase glucose uptake, including translocation of pre-existing intracellular retained populations of GLUT4 proteins to the cell surface, alterations of the intrinsic transport activity of GLUT4 proteins at the cell surface, and up-regulation of the amount of GLUT4 protein (Watson and Pessin, 2001). Although these mechanisms are not mutually exclusive, the first model has been the most intensively studied. It is well established that participation of PI3K and its downstream targets, AKT and the atypical protein kinase C (PKC) isoforms 
and 
, are involved in insulin-induced GLUT4 redistribution to the plasma membrane in adipocytes and myocytes (Martin et al., 1996; Bandyopadhyay et al., 1999; Cho et al., 2001). Concerning the second model, a potential role for p38MAPK in the activation of the GLUT4 transporter by insulin, independent of GLUT4 translocation to the plasma membrane, was proposed in 3T3-L1 adipocytes and L6 myotubes (Sweeney et al., 1999), although the contribution of this pathway was subsequently refuted (Antonescu et al., 2005). Regarding the third mechanism, the expression of GLUT4 is subject to tissue-specific hormonal and metabolic regulation (Charron et al., 1999). Studies in vivo clearly indicate that GLUT4 gene expression is down-regulated in states of relative insulin deficiency, such as streptozotocin-induced diabetes and chronic fasting, the latter being a situation that is reversed by insulin treatment and refeeding (Sivitz et al., 1989). However, studies in cells failed to establish a stimulatory role of insulin on GLUT4 expression, suggesting that additional factors could be involved in this tissue. In this regard, dexamethasone, a synthetic glucocorticoid, has been shown to increase GLUT4 mRNA transcription in myocytes and white adipocytes (Hajduch et al., 1995; Tortorella and Pilch, 2002). Furthermore, dexamethasone acts as a coregulator with insulin to induce GLUT4 mRNA transcription in brown adipocytes (Hernandez et al., 2003a).
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OBESITY, INFLAMATION, AND INSULIN RESISTANCE |
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). Insulin resistance is usually compensated for by hyperinsulinemia. Although moderate hyperinsulinemia might be tolerated in the short term, chronic hyperinsulinemia exacerbates insulin resistance and contributes directly to beta-cell failure and diabetes (White, 2003). At the molecular level, insulin resistance correlates with impaired insulin signaling in peripheral tissues. Insulin resistance in adipose tissues leads to an increase of lipolysis, with subsequent release of glycerol and FFA into the circulation. It is widely accepted that increased availability and utilization of FFA contribute to the development of skeletal muscle insulin resistance, as well as to increased hepatic glucose production (White, 2003). Both genetic and environmental factors can contribute to the development of insulin resistance, and in the latter group, obesity has been proposed to be an important contributor.
Obesity is a risk factor for the development of type 2 diabetes, in part owing to the fact that adipose tissue secretes proteins called adipokines that may influence insulin sensitivity. Adipose tissue, in particular, the visceral compartment, is now recognized as the primary contributor to the insulin resistance syndrome (Kahn and Flier, 2000). Several factors secreted from adipose tissue, including cytokines, chemokines, and FFA, can impair insulin signaling to alter insulin-mediated processes, including glucose homeostasis and lipid metabolism (Ryden et al., 2002). Accordingly, obesity is now being considered a chronic state of low-intensity inflammation. On the other hand, a recent study revealed that obesity is also associated with an increase in adipose tissue infiltration of macrophages, which contributes to the inflammatory process through the additional secretion of cytokines (Lumeng et al., 2007). The mechanisms by which WAT recruits and maintains macrophages could involve expression of monocyte chemoattractant proteins and intercellular adhesion molecule-1, as was described recently (Brake et al., 2006; Weisberg et al., 2006). Tumor necrosis factor (TNF)- has been proposed as a link between adiposity and the development of insulin resistance, because the majority of type 2 diabetic subjects are obese, TNF- is highly expressed in adipose tissues of obese subjects (Hotamisligil et al., 1995), and obese mice lacking either TNF- or its receptors showed protection against developing insulin resistance (Uysal et al., 1997). Rather than acting systemically, TNF- seems to act locally at the site of WAT through autocrine or paracrine mechanisms or both, having effects on insulin resistance and inducing IL-6 (Arner, 2003).
On the other hand, TNF- has lipolytic and antiadipogenic effects on WAT (Ruan et al., 2002). This paradox could be due to the proliferative and antiapoptotic effects of this cytokine in the obese adipocyte, and could be mediated by the differential expression of its soluble and membrane-anchored receptors. Both ceramides and FFA were reported to induce insulin resistance in peripheral tissues, and the production of these molecules could be the consequence of activation of sphingo-myelinase or lipolysis by TNF- (Arner, 2003). Several other mediators that are activated in response to TNF-, such as stress kinases and inflammatory pathways, could also contribute to insulin resistance (Hotamisligil, 2003). In this regard, increased phosphorylation of p38MAPK in human adipocytes and muscle from type 2 diabetic subjects has been reported (Carlson et al., 2003).
Direct exposure of isolated cells to TNF- inhibits insulin signaling and induces a state of insulin resistance in several systems, including 3T3-L1 cells and human primary adipocytes (Hotamisligil et al., 1996) by affecting IRS proteins. The mechanisms affecting IRS involve proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and Ser phosphorylation of IRS-1, which converts IRS-1 to a form that inhibits IR Tyr kinase activity, as reviewed previously (White, 2003; Pirola et al., 2004). Both ERK and c-Jun N-terminal kinase (JNK) have been proposed as mediating TNF- Ser-Thr phosphorylation of IRS-1 in white adipocytes (Rui et al., 2001), with the Ser307 residue being identified as the site for TNF- phosphorylation of IRS-1 (Aguirre et al., 2002). In this regard, ablation of jnk1 decreases the development of insulin resistance associated with dietary obesity (Hirosumi et al., 2002). Furthermore, ERK and p38MAPK could inhibit insulin signaling by TNF- at the level of IRS-1 and IRS-2 in 3T3-L1 adipocytes (Engelman et al., 2000; Fujishiro et al., 2003), whereas JNK could mediate the feedback inhibitory effect of insulin (Lee et al., 2003). Other work has also implicated activation of inhibitor kB kinases (IKK) by TNF- on Ser phosphorylation of IRS-1 (Yuan et al., 2001). Meanwhile, IKK inhibition with salicylate or targeted disruption of ikkβ reversed obesity and diet-induced insulin resistance (Yuan et al., 2001; Gao et al., 2003). Our group has explored in depth the mechanism by which TNF- produces insulin resistance by examining glucose uptake in 2 physiological models: murine neonatal myocytes and fetal brown adipocytes.
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INSULIN RESISTANCE BY TNF- IN MYOCYTES: AMELIORATION BY TREATMENT WITH SALICYLATE
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), which is accomplished by activation of PI3K, AKT, and several PKC isoforms, including , , , and 
(Wang et al., 1999; Rosenzweig et al., 2002; Vollenweider et al., 2002). Moreover, skeletal muscle has an insulin-independent mechanism to increase glucose transport that involves the activation of adenosine monophosphate-activated protein kinase by stimuli such as exercise, hypoxia, or ischemia (Fujii et al., 2006). The AKT substrate of 160 kDa (AS160) has emerged recently as a point of convergence for both effectors of glucose transport and seems to modulate GLUT4 trafficking (Fujii et al., 2006). Whereas the GLUT4 protein content is normal in muscle from subjects with type 2 diabetes, the capacity of insulin to stimulate translocation of GLUT4 to the plasma membrane is impaired. In contrast to the effect of insulin, contraction-stimulated glucose uptake and GLUT4 translocation in diabetic patients is normal, providing evidence that exercise might be able to bypass defects in insulin signaling (Fujii et al., 2006).
Both genetic and environmental factors have been identified as contributing to insulin resistance in skeletal muscle. The genetic approach shows that selective targeted disruption of the IGF-I and IR genes, or the GLUT4 gene, in murine skeletal muscle causes insulin resistance and insulin intolerance (Bruning et al., 1998; Zisman et al., 2000; Fernandez et al., 2001). Furthermore, IRS-1 is the key mediator of insulin action in muscle because IRS-1-deficient mice show insulin resistance in muscle (Araki et al., 1994). In this regard, IRS-1 silencing, by using small interfering RNA, caused a marked reduction in insulin-inducing actin remodeling and GLUT4 translocation, but silencing IRS-2 was without effect (Huang et al., 2005). Among the environmental factors, adipokines secreted by adipocytes, macrophages, or both in the obese state are the main candidates. In this regard, TNF- blocks skeletal muscle differentiation, causes sarcopenia, and produces insulin resistance in skeletal muscle of healthy humans and in primary cultures of mouse skeletal muscle (Rosenzweig et al., 2002; Plomgaard et al., 2005). Although ceramide and FFA have been reported to produce insulin resistance in skeletal muscle (Hajduch et al., 2001), a direct effect of TNF- in this tissue has been a matter of controversy. Several studies did not detect an inhibitory action of TNF- on insulin-induced glucose uptake, although TNF- increased basal glucose uptake substantially (Nolte et al., 1998). However, others observed an inhibitory effect of TNF- on insulin action without modifying basal glucose uptake in muscle cells (Rosenzweig et al., 2002). Moreover, in most of these studies insulin stimulation of glucose uptake was very poor because virtually all cultured skeletal muscle cell lines, including L6 and C2C12 myotubes, have been found to be deficient in GLUT4 expression.
Consequently, in our laboratory, we developed primary cultures of neonatal rat skeletal muscle that represented a suitable system for investigating the molecular basis of TNF--induced insulin resistance. When these cells were differentiated until the formation of myotubes in low-serum medium and then maintained in low-glucose medium to mimick the physiological environment, they responded to acute insulin stimulation by increasing glucose uptake and GLUT4 translocation to plasma membrane (de Alvaro et al., 2004). Chronic exposure to TNF- impaired both insulin-stimulated glucose uptake and GLUT4 translocation, without affecting the content of GLUT4 protein or the state of differentiation of the myotubes (de Alvaro et al., 2004), in agreement with the effect produced in muscle in vivo (Ruan et al., 2002). The molecular mechanism underlying TNF--mediated insulin resistance could involve activation of stress kinases and proinflamatory pathways, as was observed in neonatal myotubes (de Alvaro et al., 2004). Acute insulin stimulation also produced a transient phosphorylation of p38MAPK (Conejo et al., 2002), but insulin activated the isoform, whereas TNF- activated the β isoform (de Alvaro et al., 2004). When chemical inhibitors were used to evaluate the contribution of sustained activation of stress kinases by TNF- to insulin resistance, only the inhibition of p38MAPK completely restored insulin-stimulated glucose uptake and insulin signaling (de Alvaro et al., 2004). In this regard, adenovirus-mediated transfections of constitutively active MKK6/3 mutants in L6 myotubes were reported to diminish glucose transport induced by insulin via down-regulation of GLUT4 gene expression (Engelman et al., 2000; Fujishiro et al., 2003). Furthermore, the Ser307 residue of IRS-1 seems to be one of the residues phosphorylated by TNF- via p38MAPK, although other residues in either IRS-1, IRS-2, or IR cannot be excluded. The role of p38MAPK in inflamatory diseases, including obesity and cardiovascular dysfunction, is well recognized because this kinase regulated the biosynthesis of proinflamatory cytokines, as well as being involved in the signaling transduction pathways activated by cytokines, as elegantly reviewed by Cuenda and Rousseau (2007).
Several reports have also implicated IKK activation by TNF- on Ser phosphorylation of IRS-1, and aspirin rescues insulin-induced glucose uptake in 3T3-L1 adipocytes treated with TNF- (Yuan et al., 2001; Gao et al., 2003). In this regard, activation of IKK dependent on the functionality of p38MAPK was observed during chronic treatment with TNF- in neonatal myotubes (de Alvaro et al., 2004). These results are consistent with the requirement of p38MAPK in the activation of nuclear factor 
B in response to IL-1β (Madrid et al., 2001). Moreover, inhibition of IKK activation with salicylate completely restored insulin signaling to normal levels, despite the presence of TNF- (de Alvaro et al., 2004), but salicylate does not affect p38MAPK activation by TNF-. Thus, IKK could act downstream of p38MAPK and could mediate TNF--induced insulin resistance on skeletal muscle, as summarized in Figure 1.
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LACK OF PTP1B CONFERS PROTECTION AGAINST TNF--INDUCED INSULIN RESISTANCE IN SKELETAL MUSCLE
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; Wu et al., 2001). Moreover, noncoding polymorphisms in the PTP1B gene have been found in different populations displaying increased phosphatase muscle expression and being associated with insulin resistance (Bento et al., 2004). In this regard, transgenic overexpression of PTP1B in muscle causes insulin resistance, showing impaired insulin signaling and decreased glucose uptake in this tissue (Zabolotny et al., 2004). By contrast, mice lacking PTP1B exhibit increased insulin sensitivity at 12 wk of age (attributable to enhanced phosphorylation of the IR in liver and skeletal muscle), resistance to weight gain on a high-fat diet, and an increased basal metabolic rate (Elchebly et al., 1999; Klaman et al., 2000). The PTP1B-deficient mice had circulating insulin concentrations that were about one-half those of control animals. Thus, these mice appeared to be more insulin sensitive, because they maintained lower glucose concentrations with significantly reduced amounts of insulin (Elchebly et al., 1999). In the fasted state, there were no significant differences between PTP1B-deficient and control mice in concentrations of glucose or insulin (Elchebly et al., 1999). Furthermore, PTP1B deficiency also reduced the diabetic phenotype in mice with polygenic insulin resistance (Xue et al., 2007). Moreover, treatment with PTP1B antisense oligonucleotide improved insulin sensitivity in genetically diabetic db/db mice and increased insulin signaling in WAT and liver in genetically obese ob/ob mice (Zinker et al., 2002; Gum et al., 2003). Conversely, suppression of PTP1B in mouse embryo fibroblasts increased insulin signaling (Galic et al., 2005).
The fact that primary neonatal myotubes (developed in our laboratory) have provided a unique tool for in vitro study of insulin sensitivity (de Alvaro et al., 2004) prompted us to generate immortalized myocytes from wild-type and PTP1B-deficient neonates. Cell lines lacking PTP1B displayed enhanced insulin sensitivity in IR autophosphorylation and downstream signaling, including IRS-1 and IRS-2 Tyr phosphorylation, PI3K-associated activation, and AKT Ser-Thr phosphorylation (Nieto-Vazquez et al., 2007). The phosphorylation was detected at lower insulin doses and at shorter times in PTP1B-deficient cells than in wild-type cells (Nieto-Vazquez et al., 2007). Because activation of PI3K and AKT controls glucose transport, we detected increased insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane in PTP1B–/– cells vs. wild-type cells (Nieto-Vazquez et al., 2007). This result was expected because decreased glucose uptake in skeletal muscle was observed when PTP1B was overexpressed selectively in muscle of transgenic mice (Zabolotny et al., 2004). Moreover, recent results indicate that muscle-specific PTP1B–/– mice exhibited improved systemic insulin sensitivity and enhanced glucose tolerance when on a high-fat diet (Delibegovic et al., 2007).
Given that TNF- is a strong candidate for producing insulin resistance in skeletal muscle for the reasons mentioned above, the lack of PTP1B might confer protection against TNF--induced insulin resistance. In this regard, chronic exposure to TNF- did not induce insulin resistance either in terms of glucose uptake or insulin signaling in PTP1B-deficient myocytes (Nieto-Vazquez et al., 2007). Moreover, PTP1B–/– mice showed complete protection against TNF--induced insulin resistance during the glucose and insulin tolerance tests (Nieto-Vazquez et al., 2007). Accordingly, the lack of PTP1B expression confers protection against TNF--induced insulin resistance in skeletal muscle either in vitro or in vivo (Nieto-Vazquez et al., 2007). However, PTP1B ablation in mice affects not only insulin sensitivity in muscle and liver, but also beta-cell function, which might be contributing to this protective effect.
We have explored whether this protection against the deleterious effect of TNF- was the molecular consequence of enhanced insulin signaling provoked by PTP1B deficiency or was produced by direct abolition of some effects of TNF-. In this regard, treatment with TNF- significantly enhanced PTP1B protein expression and activity either in neonatal myocytes or in adult mice; meanwhile, the expression of other phosphatases such as PTEN (phosphatase and tensin homolog), SH-PTP2 (protein-tyr phosphatase with SIC homology 2 domains), and protein-phosphatase 2A (PP2A) were not affected (Nieto-Vazquez et al., 2007). In consequence, the genetic ablation of PTP1B avoids this action of TNF- and ensures complete protection against insulin resistance by this cytokine. Therefore, at least part of the effects elicited by TNF- on pathways involving reversible Tyr phosphorylation may be exerted through the dynamic modulation of PTP1B expression.
Accordingly, TNF- impairs insulin action in myocytes at the level of IRS-1 by a double mechanism that involves: 1) Ser phosphorylation by IKK and p38MAPK at the Ser307 residue and 2) Tyr dephosphorylation by PTP1B. Therefore, inhibition of IKK activation with salicylate and ablation of PTP1B restores insulin sensitivity in myocytes in the presence of TNF-, as summarized in Figure 1
. In this regard, new mono- and disalicylic acid derivates have been used very recently as PTP1B inhibitors and potential antiobesity drugs (Shrestha et al., 2007).
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INVOLVEMENT OF MAPK AND PHOSPHATASES IN THE DEVELOPMENT OF INSULIN RESISTANCE BY TNF- IN BROWN ADIPOCYTES
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). However, the use of fluorodeoxyglucose positron emission tomography has revealed the presence of symmetrical areas of increased tracer uptake in the upper parts of the human body, which correspond to BAT. The human depots are located differently from those in rodents, mainly in the supraclavicular and neck regions, but not in the interscapular region (Nedergaard et al., 2007). These findings point out that BAT is present and active in a substantial fraction of adult humans and that it thus may be of metabolic significance in human physiology.
Glucose transport in brown adipocytes is maintained mainly by the activity of GLUT4, and insulin treatment stimulates glucose transport by mediating GLUT4 translocation in a PI3K-, AKT-, and PKC-dependent manner (Hernandez et al., 2001; Lorenzo et al., 2002). Furthermore, inhibition of phospholipase C 
activity prevents insulin stimulation of glucose uptake, GLUT4 translocation, and actin reorganization, indicating that phospholipase C , through the production of phosphatidic acid, is a link between IR and PKC (Lorenzo et al., 2002). In addition, IRS-2 seems to be crucial in mediating glucose uptake in brown adipocytes (Valverde et al., 1998; Teruel et al., 2001).
Tumor necrosis factor- acts as a negative regulator of adipogenic and thermogenic differentiation and induces insulin resistance in BAT (Valverde et al., 1998), in a fashion similar to that reported for 3T3-L1 cells and primary human adipocytes (Kudo et al., 2004). Moreover, TNF--induced insulin resistance of glucose uptake in brown adipocytes seems to be due to the hypophosphorylation of IR and IRS-2 in response to insulin, resulting in an impairment of IRS-2-associated PI3K activity (Valverde et al., 1998; Teruel et al., 2001). As a further step, we identified ceramide production as one of the mediators of insulin resistance by TNF-, and exogenously added C2-ceramide-inhibited AKT activity throughout a ceramide-activated phosphatase (Teruel et al., 2001). Furthermore, de novo ceramide production generated by chronic treatment with TNF- induced insulin resistance on GLUT4 gene expression in brown adipocytes by interfering with C/EBP acumulation (Fernandez-Veledo et al., 2006a). Moreover, stress kinases activated in response to TNF-, mainly ERK and p38MAPK, also contribute to insulin resistance in brown adipocyte primary cultures (Hernandez et al., 2004).
Recently, a significant enhancement of PTP1B mRNA, protein, and activity was observed in brown adipocytes treated with TNF- (Fernandez-Veledo et al., 2006b), indicating that this phosphatase might contribute to the pathogenesis of TNF- in these cells. As expected, the lack of PTP1B in these cells conferred protection against TNF--induced insulin resistance on glucose uptake and insulin signaling (Fernandez-Veledo et al., 2006b).
A complex mechanism impairs the normal response to insulin on GLUT4 translocation in brown adipocytes in the presence of TNF-. This mechanism includes 1) potential Ser-Thr phosphorylation of IRS-2 by MAPK, thereby weakening the Tyr phosphorylation induced by insulin; 2) generation of ceramide and activation of PP2A, maintaining AKT in an inactive dephosphorylated state; and 3) modulation of PTP1B protein expression and activity, as summarized in Figure 2.
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PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR AND LIVER X RECEPTOR AGONISTS AMELIORATE TNF--INDUCED INSULIN RESISTANCE IN BROWN ADIPOCYTES
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that display insulin-sensitizing actions across a wide spectrum of insulin-resistant states, and have been introduced recently as therapeutic agents for the treatment of type 2 diabetes (Olefsky, 2000). Moreover, PPAR plays a critical role in the adipogenic differentiation process because its deletion in WAT resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of FFA, and decreased levels of plasma leptin (Evans et al., 2004). Adipose-specific PPAR-deficient mice showed insulin resistance and were more susceptible to high-fat diet-induced liver steatosis (He et al., 2003). Thus, TZD may exert effects on adipogenesis and gene expression, such as formation of new, small, and insulin-sensitive fat cells, reduced production of TNF-, and increased expression of adiponectin in WAT (Olefsky, 2000). Moreover, TZD up-regulated lipoprotein lipase and hormone-sensitive lipase gene expression and increased insulin responsiveness in lipolysis and lipogenesis in human subcutaneous adipocytes, consistent with the weight gain observed during the treatment (Guan et al., 2002). Nevertheless, the mechanisms by which TZD increases insulin sensitivity are still unclear. Rosiglitazone reduced circulating levels of FFA and potentiated insulin-stimulated AKT phosphorylation in WAT and muscle from Zucker obese rats (Jiang et al., 2002). Moreover, other evidence favors effects of TZD on glucose uptake by modulating changes at the level of expression of IRS-2, p85-PI3K, GLUT4, or GLUT1, either in white adipocytes or muscle cells (Evans et al., 2004). However, several limitations of this therapy, such as increased adiposity, secondary insulin resistance in WAT, and pro- and antiatherogenic effects, are currently emerging.
Liver X receptor is expressed predominantly in liver, WAT, and macrophages, and is activated by naturally produced oxysterols, as well as by synthetic compounds, such as T0901317 and GW3965 (Steffensen and Gustafsson, 2004). Although LXR function has been elucidated in detail with respect to cholesterol and lipid metabolism, new findings have emerged indicating that LXR are important regulators of glucose metabolism (Steffensen and Gustafsson, 2004). Recent studies have reported low plasma glucose, improved glucose tolerance, and increased glucose-induced insulin secretion by pancreatic islets in genetic and dietary models of type 2 diabetes treated with synthetic LXR agonists. Several lines of evidence indicate that LXR activity may be important in WAT; these nuclear receptors are abundant preferentially in subcutaneous fat (Steffensen and Gustafsson, 2004), LXR expression is regulated by the key adipocyte transcription factor PPAR, and many LXR target genes also are highly expressed in adipocytes (Juvet et al., 2003). Moreover, ligand activation of LXR regulates the expression of GLUT4 in vivo, as well as in murine and human adipocytes, through direct interaction with a conserved LXR response element in the GLUT4 promoter. In addition, the ability of LXR ligands to regulate GLUT4 expression was abolished in mice lacking LXR (Juvet et al., 2003).
Brown adipose tissue is also a target tissue for agonists of nuclear receptors because the members of the nuclear receptor family, PPAR, LXR, and LXRβ, are highly expressed in BAT (Steffensen and Gustafsson, 2004). In this regard, the PPAR agonist rosiglitazone up-regulates the expression of lipoprotein lipase, hormone-sensitive lipase, and uncoupling-protein-1 in brown adipocytes (Teruel et al., 2005) and produces insulin sensitization by increasing the expression of IR and its Tyr kinase activity (Hernandez et al., 2003b). Rosiglitazone was effective in treating TNF--induced insulin resistance in these cells because this TZD impaired the activation of p38MAPK and ERK produced by TNF- and restored the insulin-signaling cascade, leading to normalization of insulin-induced glucose uptake (Hernandez et al., 2004). Furthermore, rosiglitazone decreased the activity of PTP1B (Hernandez et al., 2003b) and improved insulin sensitivity concomitant with an increase in thermogenic differentiation, contributing globally to an accelerated glucose disposal in BAT. Moreover, recent studies demonstrated that levels and activities of PTP1B in skeletal muscle and liver of diabetic rats were increased, whereas rosiglitazone treatment attenuated these increases in muscle but not in liver (Wu et al., 2005). On the other hand, synthetic LXR agonists ameliorated TNF--induced insulin resistance in fetal brown adipocytes and completely restored insulin-stimulated GLUT4 translocation to the plasma membrane. This effect was parallel to the recovery of the insulin-signaling cascade IR/IRS-2/PI3K/AKT in the presence of TNF-, and could be due to T0901317 preventing the increase in PTP1B expression produced by this cytokine (Fernandez-Veledo et al., 2006b), in support of the hypothesis that nuclear receptors LXR are interesting targets for drug treatment of insulin-resistant conditions. Therefore, inhibition of ERK and p38MAPK activation with rosiglitazone and down-regulation of PTP1B with either rosiglitazone or LXR agonists restores insulin sensitivity in brown adipocytes in the presence of TNF-, as summarized in Figure 2.
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CONCLUSIONS |
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produces insulin resistance in murine skeletal muscle and in BAT shows tissue specificity. Tumor necrosis factor- impairs insulin-stimulated glucose uptake in myocytes at the level of IRS-1 by a double mechanism that involves Ser phosphorylation (by IKK and p38MAPK) at the Ser307 residue and Tyr dephosphorylation (by PTP1B), thereby weakening the Tyr phosphorylation induced by insulin. Consequently, pharmacological inhibition of IKK with salicylate and ablation of PTP1B restores insulin sensitivity in the presence of the cytokine. In brown adipocytes, TNF--induced insulin resistance involves Ser-Thr phosphorylation of IRS-2 by MAPK and activation of the phosphatases PP2A and PTP1B, which inactivate AKT and IR-IRS, respectively. Pharmacological inhibition of MAPK and phosphatases with rosiglitazone and LXR agonists, respectively, recovers insulin sensitivity in the presence of TNF-.
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Footnotes |
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2 Presented at the Triennial Growth symposium at the annual meeting of the American Society of Animal Science, San Antonio, TX, July 8 to 12, 2007.
3 Corresponding author: mlorenzo{at}farm.ucm.es
Received for publication July 27, 2007. Accepted for publication October 11, 2007.
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LITERATURE CITED |
|---|
. Mol. Endocrinol. 13:1766–1772.B through an AKT/P70S6K/p38-MAPK pathway. Oncogene 21:3739–3753.[CrossRef][Medline]B and downregulation of AP-1 activities. J. Cell. Physiol. 186:82–94.[CrossRef][Medline] produces insulin resistance in skeletal muscle by activation of inhibitor B kinase in a p38 MAPK-dependent manner. J. Biol. Chem. 279:17070–17078.-mediated insulin resistance, but not dedifferentiation, is abrogated by MEK1/2 inhibitors in 3T3-L1 adipocytes. Mol. Endocrinol. 14:1557–1569.-induced insulin resistance on GLUT4 gene expression in brown adipocytes. Arch. Physiol. Biochem. 112:13–22.[CrossRef][Medline]-induced insulin resistance in murine brown adipocytes by down-regulating protein tyrosine phosphatase-1B gene expression. Diabetologia 49:3038–3048.[CrossRef][Medline] knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl. Acad. Sci. USA 100:15712–15717.. Biochem. J. 372:617–624.[CrossRef][Medline] in human obesity and insulin resistance. J. Clin. Invest. 95:2409–2415.[Medline]- and obesity-induced insulin resistance. Science 271:665–668.[Abstract] agonists. Diabetes 51:2412–2419.2 gene expression by tumor necrosis factor via an inhibition of CCAAT/enhancer-binding protein during the early stage of adipocyte differentiation. Endocrinology 145:4948–4956. participates in insulin stimulation of glucose uptake through activation of PKC in brown adipocytes. Exp. Cell Res. 278:146–157.[CrossRef][Medline]B through utilization of the IB kinase and activation of the mitogen activated protein kinase p38. J. Biol. Chem. 276:18934–18940.-induced insulin resistance. Diabetes 56:404–413. does not affect insulin-stimulated glucose uptake in skeletal muscle. Diabetes 47:721–726.[Abstract] agonists. J. Clin. Invest. 106:467–472.[Medline] induces skeletal muscle insulin resistance in healthy human subjects via inhibition of AKT substrate 160 phosphorylation. Diabetes 54:2939–2945. on protein kinase C isoforms and mediate inhibition of insulin receptor signaling. Diabetes 51:1921–1930.: Implications for insulin resistance. Diabetes 51:3176–3188. stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J. Clin. Invest. 107:181–189.[CrossRef][Medline]-mediated lipolysis in human fat cells. J. Biol. Chem. 277:1085–1091. in brown adipocytes by maintaining AKT in an inactive dephosphorylated state. Diabetes 50:2563–2571. function. Nature 389:610–614.[CrossRef][Medline] causes insulin receptor substrate-2-mediated insulin resistance and inhibits insulin-induced adipogenesis in fetal brown adipocytes. Endocrinology 139:1229–1238./) activation in myotubes from obese patients with impaired glucose tolerance. Diabetes 51:1052–1059.This article has been cited by other articles:
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  S. S. Chung, M. Kim, B.-S. Youn, N. S. Lee, J. W. Park, I. K. Lee, Y. S. Lee, J. B. Kim, Y. M. Cho, H. K. Lee, et al. Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor {gamma} in Human Skeletal Muscle Cells Mol. Cell. Biol., January 1, 2009; 29(1): 20 - 30. [Abstract] [Full Text] [PDF]
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Abstract
INTRODUCTION
