Gaens, Katrien HJ.a,b; Stehouwer, Coen DA.a,b; Schalkwijk, Casper G.a,b
Obesity is associated with an increased risk of developing insulin resistance, type 2 diabetes, fatty liver disease, hypertension and (cardio) vascular complications . Production and secretion of proinflammatory and anti-inflammatory cytokines from the adipose tissue, known as adipokines, contribute directly to the burden of obesity-related complications . However, the underlying mechanism by which obesity leads to dysregulation of adipokine secretion remains to be elucidated.
Increased formation of advanced glycation endproducts (AGEs)/advanced lipoxidation endproducts (ALEs) occurs in diverse settings, such as diabetes and aging. In the complex pathways of AGEs/ALEs formation, hyperlipidemia, hyperglycemia and oxidative stress, all characteristic features of obesity, play an important role. Therefore, AGEs/ALEs might accumulate under conditions of obesity. Various detrimental effects of AGEs/ALEs in multiple tissues have been described, such as induction of inflammatory responses and oxidative stress [3–5]. A key mechanism by which AGEs exert these maladaptive effects is via the activation of the receptor for advanced glycation endproducts (RAGE).
The role of AGEs/ALEs and RAGE in obesity and obesity-related complications is receiving increased attention. This review will focus primarily on the formation of AGEs/ALEs in obesity and their recently discovered obesity-related biological effects, notably dysregulation of adipokine secretion.
FORMATION OF ADVANCED GLYCATION ENDPRODUCTS
AGEs are stable endproducts of a nonenzymatic glycation reaction, also known as the Maillard reaction. The formation of these post-translational modifications of proteins starts with a nonenzymatic condensation reaction of the dicarbonyl group of sugar aldehydes, such as glucose, with the N-terminus of free-amino groups of proteins, resulting in the rapid formation of a Schiff base. These labile adducts then undergo rearrangements to more stable Amadori products. Only a small part of these Amadori products undergo further irreversible chemical reactions leading to the formation of AGEs [6,7]. Due to the possible variation in aldehydes and amines, and the variety and complexity of downstream reactions, AGEs represent a heterogeneous group of chemical modifications of proteins. Major AGEs are Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL) and the crosslinker pentosidine. The formation of AGEs proceeds over a long time, and because of their slow formation, it was long believed that AGEs accumulate only on long-lived extracellular proteins . However, rapid AGE formation by reactive dicarbonyl compounds is currently believed to be one of the major routes in vivo. These reactive dicarbonyl compounds, such as methylglyoxal (MGO), glyoxal and 3-deoxyglucosone (3DG), are formed from glucose-derived glycolytic intermediates, such as glyceraldehydes-3-phosphate, and may react with proteins resulting in a very fast formation of specific AGEs within hours . Glucose-derived glycolytic intermediates not only form AGEs more rapidly, but also more abundantly as compared to glucose . Among the reactive dicarbonyl compounds, MGO is believed to be the most potent glycation agent [11,12].
FORMATION OF ADVANCED LIPOXIDATION ENDPRODUCTS
Beside sugars and glucose-derived glycolytic intermediates, other sources have been described as precursors in the formation of AGEs, including products derived from lipid peroxidation [13–16]. Lipid peroxidation of polyunsaturated fatty acids leads to the formation of dicarbonyl compounds, some of which are identical to those formed from glucose-derived glycolytic intermediates, such as MGO and glyoxal, and others are more specific for lipid peroxidation, such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) [17,18]. These reactive dicarbonyl compounds may react with amino acids in proteins resulting in the formation of ALEs. Modification of proteins originating from lipid peroxidation reactions produces characteristic ALEs, such as MDA-lysine and HNE-lysine, but also CML and CEL . Thus, some protein modifications, such as CML, can be regarded as AGEs and ALEs because they are formed on proteins by both glucose-derived glycolytic intermediates and lipid peroxidation products . The formation of identical reactive dicarbonyl compounds demonstrates the strong interplay between the formation of AGEs and ALEs. A schematic overview of the three major routes of AGE/ALE formation is given in Figure 1.
Formation of AGEs/ALEs is a naturally occurring process and is the result of normal metabolism. Increased formation of AGEs/ALEs occurs under physiological circumstances of aging, under hyperglycemic conditions as well as under conditions of increased oxidative stress and hyperlipidemia. Therefore, accelerated AGEs/ALEs formation is seen in diabetes, but also in age-related diseases, such as atherosclerosis and neurodegenerative disorders including Alzheimer's disease [3,7].
In addition to the endogenous formation of AGEs in the human body, a portion of AGEs in the body may be derived from exogenous sources, for example from food. However, it is not clear to what extent AGEs are intestinally absorbed and what the contribution is of exogenous sources of AGEs to the total concentration of AGEs in the body .
BIOLOGICAL EFFECTS OF ADVANCED GLYCATION ENDPRODUCTS
Several mechanisms have been proposed by which AGEs exert harmful effects and contribute to development of pathological conditions : intracellular glycation of proteins resulting in altered functions of proteins and impaired cell function; modification of extracellular matrix proteins by AGEs resulting in abnormal interactions between proteins and cells; and binding of circulating AGEs to AGE receptors on different cell types leading to activation of intracellular signaling pathways.
Research has identified a number of AGE-binding proteins, including the RAGE, which is the best-characterized and the best-studied receptor so far [21,22]. Readers interested in the AGE–RAGE axis are referred to excellent review articles [21–23,24▪]. In brief, binding of AGEs to RAGE causes oxidative stress and activation of nuclear factor-κB (NF-κB) via activation of the p21ras and the mitogen-activated protein (MAP) kinase signaling pathways . Numerous lines of evidence indicate that the AGE–RAGE axis results in generation of proinflammatory cytokines, expression of adhesion molecules and oxidative stress [24▪]. An important downstream gene of the AGE–RAGE axis is RAGE itself, that leads to a continued maintenance and amplifications of the signaling pathways and inflammatory events . Kislinger et al. elucidated that, among all AGEs/ALEs, CML adducts in modified proteins are major ligands for RAGE and that CML could trigger signal transduction mechanism upon binding. Recent research has shown that RAGE oligomerizes on plasma membranes of human cells and that this oligomerization provides a mechanism to increase the number of binding sites. Oligomerization of RAGE is required for the high-affinity binding of ligands  and plays a critical role in activation of RAGE and induction of downstream signaling pathways. Signals that trigger oligomerization of RAGE are unknown and need to be further investigated. Lack of oligomerization of RAGE at membranes of particular cell types could explain the unresponsiveness of some cells to CML [26,27].
DEFENSE MECHANISMS AGAINST THE FORMATION OF ADVANCED GLYCATION ENDPRODUCTS
To minimize the production of AGEs/ALEs, the human body has evolved a number of enzymatic and nonenzymatic defense mechanisms [28▪,29]. The glyoxalase system, which is composed of the enzymes glyoxalase-I (GLO1) and glyoxalase-II (GLO2), is the most important mechanism that protects against AGE formation. This system is responsible for the detoxification of the reactive dicarbonyl MGO, and to a lesser extent glyoxal, thereby depleting a major pool of AGE precursors and preventing AGE formation [29,30▪]. GLO1 is considered the key enzyme in the antiglycation defense .
As GLO1 is the major detoxification enzyme for reactive dicarbonyl compounds, it is plausible that alterations in expression, protein levels and activity of GLO1 influence AGE production and hence the development of diabetic complications and age-related diseases. Indeed, Brouwers et al.[30▪] recently demonstrated, in a diabetic rat model, that overexpression of GLO1 reduced the concentration of the dicarbonyls MGO and glyoxal, and AGE levels. Overexpression of GLO1 also diminished levels of oxidative stress [30▪]. Furthermore, they showed in an ex-vivo model that hyperglycemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries can be improved by GLO1 overexpression . Enhancement of the glyoxalase pathway along with a decrease in MGO-dependent protein glycation also prevents the development of several indices of late complications [28▪,33,34,35▪▪].
INCREASED ACCUMULATION OF ADVANCED GLYCATION ENDPRODUCTS/ADVANCED LIPOXIDATION ENDPRODUCTS IN ADIPOSE TISSUE
In obesity, the combined effects of enhanced food consumption, low-energy expenditure, hyperglycemia, hyperlipidemia and increased oxidative stress may augment the formation of reactive intermediates and the formation of specific AGEs/ALEs (Fig. 2).
Formation of advanced glycation endproducts/advanced lipoxidation endproducts is increased in obesity
Peroxidation of lipids leads to the formation of reactive dicarbonyl compounds, which can react further with amino acid residues in proteins to ALEs, such as CML. Fu et al. demonstrated that CML is formed during lipid peroxidation reactions, and, furthermore, showed that lipid peroxidation reactions are a more important source for CML formation than nonenzymatic glycation. Therefore, CML is mainly regarded as an ALE, rather than an AGE. As demonstrated in Figure 3, differentiation of human preadipocytes to adipocytes is accompanied by endogenous formation of CML, indicating that fat accumulation is associated with CML accumulation. As CML is a major ALE, and is an important ligand for RAGE that can activate RAGE-dependent signaling pathways , CML may be regarded as an important protein modification in obesity with significant effects on adipose tissue and adipocyte function. In addition to CML, it has been suggested that MGO is formed by lipid peroxidation .
Accelerated endogenous formation of both CML and MGO in obesity has been described in a few studies [36▪,37,38▪,39]. Recently, we demonstrated an increased CML accumulation in fatty livers of obese patients, and the CML accumulation progressively increased with the grade of steatosis [36▪]. Increased CML accumulation was also observed in skeletal muscles of obese patients, which was associated with weight gain . A recent study demonstrated a markedly increased MGO accumulation in fat tissue of obese rats at an age of 16 weeks [38▪,39]. In addition, MGO serum levels were increased in obese Zucker rats as compared to lean rats [38▪,39]. Increased accumulation of CML and MGO-derived AGEs in obesity may thus play an important role in adipose tissue dysfunction.
The role of receptor for advanced glycation endproducts in obesity
Although increased levels of CML in different tissues in obesity has been observed, CML plasma levels seem to be decreased in obesity. Sebekova et al. found significantly lower CML plasma levels in obese children compared to lean controls. Moreover, an inverse relationship between circulating CML and fat mass was recently reported , suggesting that enlargement of adipose tissue mass in obesity contributes to decreased CML plasma levels. This lack of reflection between tissue CML and circulating CML levels is unexpected. Although the underlying mechanism is unknown, RAGE may play a role in lowering circulating CML levels. Recently, it has been reported that AGE levels in kidneys from diabetic RAGE-deficient mice were reduced compared with levels in kidneys of wild-type mice, whereas CML blood concentrations were higher in RAGE-deficient mice . This suggests that RAGE plays a role in the local accumulation of AGEs in tissues in obesity and at the same time decrease AGEs plasma levels.
Recent research suggests that RAGE itself might be involved in adiposity. Ueno et al. demonstrated that RAGE deficiency was associated with decreased fat mass and smaller adipocyte size. This corresponds with data obtained from Song et al., who demonstrated that body weight gain and increased fasting glucose by high-fat feeding is significantly less in RAGE-deficient mice. In contrast, an opposing effect of RAGE on obesity was recently described by Leuner et al., by demonstrating that female RAGE-deficient mice were heavier than female wild-type mice, whereas this effect was not found in male mice. In addition to the possible involvement of RAGE in development of obesity, Cai et al. demonstrated that oral administration of MGO in mice resulted in adiposity and obesity-related complications.
Reduction of the detoxification glyoxalase system in obesity
In addition to the accelerated endogenous formation of AGEs/ALEs, a dysregulated glyoxalase system may also contribute to accumulation of AGEs/ALEs in obesity. In animal models of obesity, GLO1 was decreased in liver , in glomeruli  and in neuronal tissue . These data indicate that GLO1 is locally decreased in most tissues in obesity. Although we recently found that differentiation of human preadipocytes to mature adipocytes was associated with reduced GLO1 expression and activity, which were accompanied by an increase of endogenous MGO-derived AGE Nε-CEL concentrations, (K. Gaens and C. Schalkwijk; unpublished results), data of GLO1 in adipose tissue are missing. Thus, further research is needed to investigate the association between obesity and GLO1.
It has recently been described that activation of RAGE is associated with decreased expression of GLO1 . AGEs have been found to significantly reduce GLO1 expression and activity in cultured fibroblasts, endothelial cells and neuronal cells, whereas inhibition of RAGE restores GLO1 in these cells [21,22]. We recently found, in cultured human adipocytes, that CML downregulated the gene expression of GLO1 via RAGE. These findings suggest that RAGE is not only a signal transducing receptor which can lead to cell activation and inflammation, but can also directly interfere with the defense system for detoxification of AGE precursors.
BIOLOGICAL EFFECTS OF ADVANCED GLYCATION ENDPRODUCTS/ADVANCED LIPOXIDATION ENDPRODUCTS IN ADIPOSE TISSUE
Adipose tissue is a major endocrine organ, which produces and secretes many biologically active molecules, known as adipokines. It has been demonstrated that inflammatory adipokines play a role in obesity-related inflammation and development of insulin resistance and type 2 diabetes in obesity [1,2]. Recent data demonstrated that AGEs/ALEs affect adipose tissue function regarding production and secretion of inflammatory adipokines. In cultured mouse adipocytes, AGEs lead to the upregulation of plasminogen activator inhibitor (PAI)-1 and monocyte chemoattractant protein (MCP)-1 [50–52], which are both implicated in the development of obesity-associated glucose intolerance. In adipose tissue, AGEs stimulated PAI-1 and MCP-1 expression via RAGE-mediated generation of oxidative stress [50,52] In addition, an AGE-induced downregulation of leptin was observed in cultured adipocytes [51,53]. Adiponectin expression levels were also decreased upon AGE incubation in adipocytes, which was mediated via RAGE-induced NADPH oxidase-generated oxidative stress . In addition to the AGE-induced downregulation of adiponectin expression, which is generally seen in insulin resistance, adiponectin itself can also be structurally modified by glycation. Glycation of adiponectin affects its function, and as such contributes to the development of insulin resistance [55–57]. Besides adipocytes, other cell types in adipose tissue may contribute to the dysregulated production and secretion of adipokines. Obesity is associated with a significant infiltration of macrophages in adipose tissue. These macrophages are a potential source of secreted inflammatory factors, and it has been demonstrated in macrophages that AGEs stimulate the production of cytokines, such as TNF-α [58,59].
In addition, the adipose tissue is also a major organ for glucose and lipid metabolism. In 3T3-L1 adipocytes, AGEs cause insulin resistance by suppressing insulin-stimulated glucose uptake, which was reversed by anti-RAGE antibody . Furthermore, the AGE–RAGE interaction inhibits glucose uptake in these adipocytes through the generation of intracellular reactive oxygen species . In obese, type 2 diabetic mice, insulin sensitivity was ameliorated by the inhibitor of AGEs/ALEs formation, pyridoxamine . There is accumulating evidence that the AGE–RAGE axis affects these processes, thus contributing to insulin resistance.
In addition to indirect effect of AGEs/ALEs on glucose metabolism leading to insulin resistance, glycation of insulin itself may change the properties of insulin [39,62]. Jia et al.[62,63] showed that MGO modification of insulin-reduced glucose uptake in 3T3-L1 adipocytes compared with native insulin, indicating that abnormalities of the insulin molecule in structure and function induced by MGO can cause the actions of insulin. Moreover, it has been demonstrated that MGO induces structural changes to insulin receptor substrate proteins in adipocytes . Taken together, it is highly likely that the AGE–RAGE axis and intracellular MGO inhibit insulin signaling and lead to insulin resistance.
There is increasing evidence that the accumulation of AGEs/ALEs in adipose tissue contributes to obesity-related complications. Increased accumulation of CML in obesity and CML-RAGE mediated activation of intracellular signaling pathways in adipocytes may stimulate inflammatory signaling in adipose tissue. The resulting dysregulation of proinflammatory and anti-inflammatory cytokines may subsequently contribute to the development of obesity-related complications. In addition, AGEs/ALEs may also directly affect glucose metabolism in adipocytes. Further research is needed to investigate whether the CML–RAGE axis, MGO and GLO1 are implicated in the pathogenesis of obesity and obesity-related complications. Identification of this mechanism may provide an important strategy for novel therapeutic approaches against obesity and obesity-related complications.
This review and the research focusing on advanced glycation endproducts in obesity was performed was part of the PREDICCt project (grant 01C-104), within the framework of CTMM, the Dutch Center for Translational Molecular Medicine (http://www.ctmm.nl). It was supported by the Netherlands Heart Foundation, Dutch Diabetes Research Foundation (grant #2005.00.035), and the Dutch Kidney Foundation.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 86–88).
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