Partner und Internationale Organisationen
(Englisch)
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AT, BE, BG, CH, CY, CZ, DE, ES, FI, FR, HU, IL, IT, NL, NO, PL, RO, RS, SE, SI, SK, TR, UK
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Abstract
(Englisch)
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Diabetes and insulin resistance is currently viewed as inflammatory diseases which are closely related to the inflammatory signals derived from the adipose tissue.?These findings are supported by the data showing that mice which lack the inflammatory mediator IKK are resistant to high fat diet induced obesity (1) . More recently, another study reported that the innate immune receptor Toll like receptor 4 (TLR4) is crucial in mediating high fat iduced inflammation, weight gain and insulin resistance (2). Moreover, several studies addressed the question of the relationship between increased adipose tissue pro-inflammatory cytokine secretion and the development of insulin resistance. By contrast, no experiments were conducted to reveal if the lack of anti-inflammatory cytokines would have similar deleterious metabolic effects. Two major anti-inflammatory cytokines are interleukin 4 and 13 (IL-4 and IL-13, respectively. They both use STAT6 as a mediator of receptor signal transduction. A previous study indicated that STAT6 knock-out mice show increased aortic lipid plaque formation when challenged by an atherogenic diet (3). The relevance of these findings were confirmed when a human study reported increased STAT6 expression in the coronary artery intima of patients with advanced atherosclerosis (4). In line with these observations, STAT6 was also shown to be protective against ischemia-reperfusion induced injury in the liver (5). The above studies demonstrated that STAT6 is involved in the regulation of metabolic adaptation under different stress conditions such as hypoxia and suggested that it might be involved in the regulation of peripherial lipid deposition. Adipose tissue differentiation is induced by the transcription factor PPAR gamma and its co-activator termed PGC-1beta. PGC-1 beta is also involved in the alternative activation of macrophages induced by IL-4 and IL-13. STAT6 has been very recently shown to play a role in this process as a partner of PGC-1 beta (6). This alternative activation process leads to the 'positive', reparative effects of macrophage activation such as wound healing and attenuated inflammatory reaction. Free radical production is an integral part of insulin signaling but if uncontrolled it can contribute to the development of metabolic syndrome (7). STAT6 can also indirectly modulate cellular levels of reactive oxygen species through the upregulation of the Arginase enzeme which will then compete for the same substrate (Arginine) as the nitric oxide synthase (NOS) thus decreasing nitric oxide production (8). Thus, STAT6 is at the crossroad of different signaling pathways: the innate and lymphocyte mediated inflammatory reactions, lipid metabolism and the production of cellular reactive oxygen species. As these processes are also important factors in the development of metabolic syndrome, it is quite relevant to ask if STAT6 might in fact be a major protector againts the onset of this complex diesase. (1) Shoelson SE, Lee J, Yuan M. (2003) Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord 27 Suppl 3: S49-52. (2) Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116: 3015-3025. (3) Huber SA, Sakkinen P, David C, Newell MK, Tracy RP. (2001) T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 103: 2610-2616. (4) Satterthwaite G, Francis SE, Suvarna K, et al. (2005) Differential gene expression in coronary arteries from patients presenting with ischemic heart disease: further evidence for the inflammatory basis of atherosclerosis. Am Heart J 150: 488-499. (5) Shen XD, Ke B, Zhai Y, et al. (2003) Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology 37: 296-303. (6) Vats D, Mukundan L, Odegaard JI, et al. (2006) Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4: 13-24. (7) Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39: 44-84. (8) Gray MJ, Poljakovic M, Kepka-Lenhart D, Morris SM, Jr. (2005) Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPbeta. Gene 353: 98-106.
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