Inflammation Research

, 58:727

The major inflammatory mediator interleukin-6 and obesity

Authors

  • Katalin Eder
    • Research Group for Inflammation Biology and ImmunogenomicsHungarian Academy of Sciences and Semmelweis University
  • Noemi Baffy
    • Department of Genetics, Cell and ImmunobiologySemmelweis University
    • Research Group for Inflammation Biology and ImmunogenomicsHungarian Academy of Sciences and Semmelweis University
    • Department of Genetics, Cell and ImmunobiologySemmelweis University
  • Andras K. Fulop
    • Department of Genetics, Cell and ImmunobiologySemmelweis University
Review

DOI: 10.1007/s00011-009-0060-4

Cite this article as:
Eder, K., Baffy, N., Falus, A. et al. Inflamm. Res. (2009) 58: 727. doi:10.1007/s00011-009-0060-4

Abstract

Adipose tissue is one of the main sources of inflammatory mediators, with interleukin-6 (IL-6) among them. Although high systemic levels of inflammatory mediators are cachectogenic and/or anorexic, today it is a widely propagated thesis that in the background of obesity, a low level of chronic inflammation can be found, with IL-6 being one of the many suggested mediators. This paper reviews the studies describing elevated IL-6 levels in obese patients and the role of adipocytes and adipose-tissue macrophages in the production of IL-6. The secretion of IL-6 is regulated by several physiologic or pathologic factors: hormones, cytokines, diet, physical activity, stress, hypoxia, and others. Adipose tissue-derived IL-6 may have an effect on metabolism through several mechanisms, including adipose tissue-specific gene expression, triglyceride release, lipoprotein lipase downregulation, insulin sensitivity, and so on. Having a better understanding of these mechanisms may contribute to the prevention and treatment of obesity.

Keywords

ObesityInterleukin-6Adipose tissueInflammationAdipokines

Introduction

More than a decade ago, while dealing with the regulation of hepatic acute-phase reaction, it was observed that one of the main sources of inflammatory mediators is adipose tissue [1]. Later, during study of a genetically modified histamine-deficient mouse strain (HDC KO), increased leptin serum level and adult obesity were found in this model [2]. Moreover, decreased interleukin-6 (IL-6) inducibility in these animals after various inflammatory challenges [3, 4] was observed. This phenomenon was in good accordance with the contemporary thesis that a high systemic level of inflammatory mediators, e.g., TNF-α, IL-1, and IL-6, has a cachectogenic and/or anorexic effect [59]. This observation was further substantiated when stronger positive correlations were found with IL-6 than TNF-α as a biomarker for subcutaneous adipose tissue (SAT), white adipose tissue (WAT), body mass index (BMI), and waist circumference (WC) [10].

In the last decade, several studies have shown elevated IL-6 levels in obese patients [11]; however, data regarding the relevance of IL-6 are controversial [1018]. This could be partially attributable to the complex etiology of obesity, consisting of the interaction of genetics, diet, and physical activity levels, additionally influenced by environmental, socioeconomic, and behavioral factors. Being obese (BMI > 30 kg/m2) is associated with an increased risk of developing insulin resistance, type 2 diabetes (T2D), accelerated atherosclerosis associated with cardiovascular disease, orthopedic problems, and other chronic diseases [19]. What is now termed the “obesity epidemic” has developed over the last two decades, with prevalence rates exceeding 30% of the adult population in some Western countries [20].

Traditionally, adipose tissue was considered to passively store triacylglycerols and release free fatty acids. Now, it is recognized to be an active endocrine organ, being a source of a large number of cytokines and bioactive mediators, generally referred to as adipokines [21]. These adipokines seem to be involved in a wide range of systemic reactions associated with hemostasis, lipid metabolism, blood pressure regulation, insulin sensitivity, and angiogenesis. There is growing evidence that obesity is a chronic inflammatory state, indicated by the increased expression, production, and release of a number of inflammation-related adipokines, including TNF-α, IL-6, PAI-1, haptoglobin, and leptin in obese individuals [22].

Human IL-6 is a single polypeptide chain of 185 amino acids that forms a bundle of four α-helices [23]. Its molecular weight ranges between 21 and 28 kDa, depending on the state of glycosylation and phosphorylation [24, 25]. It is regarded as the major inflammatory mediator having both pro- and anti-inflammatory effects [26, 27]. In healthy persons, its serum concentration is very low (average < 3–4 pg/ml, with a range of 1–9 pg/ml for lean and obese persons), but during inflammation this cytokine reaches much higher serum concentrations. It is important, however, to mention that levels of IL-6 may depend on the sampling method. Unfortunately, data in this field are conflicting. According to a brief technical paper, serum concentration of IL-6 was increased when sampled through an indwelling venous catheter [28], but in another study, the levels of TNF-α and IL-6 did not differ significantly when 11 paired samples were obtained by venous puncture and through an indwelling cannule [29]. Activated endothelial cells produce IL-6, but unfortunately, the authors are unaware of any studies where the same sampling method was used in the control (lean) and obese patients, so that the level of IL-6 could be compared independently of the sampling method. In most publications, the method of blood sampling is not described at all [30]. However, extremely high levels of IL-6 concentration have been well documented as in cases of severe stress, infection (sepsis), and major surgery, where the IL-6 concentration can reach 10- to 1,000-fold the normal level [31].

Adipose tissue as a source of IL-6

Adipose tissue can be divided into two major types: white adipose tissue (WAT) and brown adipose tissue. WAT represents the vast majority of adipose tissue in humans and is the site of energy storage, whereas the main role of brown adipose tissue is nonshivering thermogenesis, particularly in small mammals and human neonates. In WAT, mature adipocytes are by far the largest in size, but their abundance depends on the specific adipose depot and species. Hauner reported that human adipocytes represent approximately 50–70% of the cells in human WAT. In contrast, Fain et al. [32] reported that approximately 70% of the protein from human WAT digests is associated with tissue matrix, and the remaining 30% was equally divided between stromal vascular (SV) cells and floating adipocytes [33]. WAT produces a number of adipokines linked to inflammation, including adiponectin, IL-1β, IL-6, TNF-α, MCP-1, and MIF. Circulating levels of TNF-α and IL-6 are directly correlated with adiposity and insulin resistance [34].

In circulating blood, 15–35% of total (noninflammatory) IL-6 concentration has been estimated to originate from adipose tissue [29]. The adipocytes themselves can produce and secrete IL-6 [35, 36], but they may only contribute to a fraction of total IL-6 released by the adipose tissue [32, 37] since nonfat cells in the adipose tissue matrix and SV cells are also capable of producing it. Visceral adipose tissue explants release more IL-6 than do explants of subcutaneous (sc) adipose tissue [32]. Plasma IL-6 levels published in different studies were variable. In healthy lean patients (BMI <30), ≈1 pg/ml was found, and in obese, but otherwise healthy, patients ≈3 pg/ml was measured [38]. In other studies, plasma IL-6 was undetectable (<l pg/mL) [39] or ranged from undetectable to 4.3 pg/ml [40] in healthy individuals. The production site of IL-6 is not the only variable factor—the levels of IL-6 show a circadian rhythm [29]. In vivo release of IL-6 by human sc adipose tissue is greater in the evening compared to around noon. The release of IL-6 into the systemic circulation and the fact that this release is greater in obese subjects support a possible novel role for IL-6 as a systemic regulator of body weight and lipid metabolism [29].

Adipose tissue macrophages

In addition to adipocytes, adipose tissue also contains pre-adipocytes, endothelial cells, fibroblasts, leukocytes, and most importantly, macrophages. Adult human WAT has been reported to be composed of approximately 1–30% infiltrated macrophages besides adipocytes and tissue matrix.

Obesity induces adipose tissue macrophage (ATM) infiltration in WAT. The number of macrophages present in WAT is directly correlated with adiposity and with adipocyte size in both human subjects and mice, with no significant differences present between subcutaneous and visceral WAT. These cells are a significant source of TNF-α and IL-6. In fact, macrophages are the major source of TNF-α produced by WAT and contribute approximately 50% of WAT-derived IL-6 [41].

Regulation of IL-6 production

Effect of hypoxia and stress

A central question is why WAT releases proinflammatory cytokines. A possible explanation is the response to hypoxia in areas of fat depots as the tissue mass increases during the progression of obesity. The following may be the sequence of events: as the adipose tissue expands, there is insufficient vasculature to maintain normoxia throughout the organ, clusters of adipocytes then become relatively hypoxic, and an inflammatory response ensues that serves to increase blood flow and to stimulate angiogenesis [42]. A pivotal signal in the cellular response to hypoxia is hypoxia-inducible factor-1 (HIF-1) [43]. HIF-1 expression is evident in human adipocytes, as noted previously in murine fat cells, and both the levels of mRNA and protein fall after the induction of differentiation. Hypoxia results in an increase in the amount of the HIF-1α protein in cultured fat cells. HIF-1 is composed of two subunits, HIF-1β, which is constitutively expressed, and HIF-1α, which is recruited in response to low O2 tension to yield the functional transcription factor. Hypoxia stabilizes HIF-1α protein, which is otherwise (under normoxic conditions) degraded by an ubiquitin-dependent proteasome. Total HIF-1α protein level in human adipocytes increases rapidly and substantially under hypoxic conditions, both with 1% O2 and by treatment with CoCl2 [44]. Hypoxia-stimulated expression of the genes encoding IL-6, and leptin as well as the release of the IL-6 are also significantly upregulated. MIF, a potent macrophage migration inhibitory factor that is secreted from human adipocytes, is also stimulated by hypoxia. MIF may also play an important role in enhancing macrophage recruitment. Thus, hypoxia can directly affect key components of the inflammatory cascade within adipose tissue [44]. Hypoxia may underlie the inflammatory response in adipose tissue observed in obesity, with a potential causal role in the development of obesity-associated diseases.

Furukawa et al. [45] have demonstrated that in nondiabetic human subjects, fat accumulation closely correlates with the markers of systemic oxidative stress. They also showed that plasma adiponectin levels correlate inversely with systemic oxidative stress. In cultured adipocytes, addition of oxidative stress suppressed mRNA expression and secretion of adiponectin, and it also increased PAI-1, IL-6, and MCP-1 mRNA expression [45]. H2O2 production was increased only in adipose tissue of obese mice, but not in other tissues examined, including the liver, skeletal muscle, and aorta. These results suggest that adipose tissue is the major source of the elevated plasma ROS. Adipose NADPH oxidase is elevated and contributes to ROS production in accumulated fat, suggesting that in accumulated fat, elevated levels of fatty acids activate NADPH oxidase and induce ROS production [45]. On the other hand, dissipation of ROS results in decreased IL-6 secretion in 3T3-L1 adipocytes. It is possible that increased ROS production and MCP-1 secretion from accumulated fat could cause infiltration of macrophages and inflammation in the adipose tissue of obese individuals. It is worth mentioning that hyperglycemia can also trigger increased levels of reactive oxygen species. Exposure to hyperglycemic conditions results in increased IL-6 secretion in 3T3-L1 adipocytes [46].

Obesity is also associated with mechanical stress, excess lipid accumulation, abnormalities in intracellular energy fluxes, and nutrient availability. To examine whether endoplasmic reticulum (ER) stress is increased in obesity, Ozcan et al. [47] investigated the expression patterns of several molecular indicators of ER stress in dietary [high-fat diet (HFD)-induced] and genetic (ob/ob) models of murine obesity. The pancreatic ER kinase or PKR-like kinase (PERK) is an ER transmembrane protein kinase that phosphorylates the α subunit of translation initiation factor 2 (eIF2α) in response to ER stress. The phosphorylation status of PERK and eIF2α is therefore a key indicator of the presence of ER stress. Their experiments demonstrated increased PERK and eIF2α phosphorylation in liver extracts of obese mice compared with lean controls.

The major link between stress and IL-6 is NF-κB (nuclear factor-kappaB). NF-κB is a transcription factor that resides in the cytoplasm of cells and is translocated to the nucleus when activated. Its activation is induced by a wide variety of agents including stress, cigarette smoke, infections, other inflammatory stimuli (endotoxins, cytokines, free radicals), and carcinogens. On activation, NF-κB regulates the expression of almost 400 different genes, including IL-6 [48]. Further details are discussed in a recent review [49]. The other link between stress and inflammation is the activation of protein kinase c-Jun NH2-terminal kinase 1 (JNK1) in adipocytes, which results in an increased concentration of circulating IL-6 [50]. These results suggest an initial effect of stress and hypoxia in the development of the pro-inflammatory state found in obesity, however, further studies will be needed to clarify the exact molecular mechanisms.

Effects of inflammation

There is growing evidence that obesity is characterized by a state of chronic low-grade inflammation, so it is not surprising that inflammatory reactions and cytokines can regulate IL-6 production. A clinical study on 20 healthy volunteers demonstrated, for the first time, that injection of LPS increased both systemic and adipose tissue levels of TNF and IL-6 and caused insulin resistance [51]. Additionally, more and more in vitro experiments show that mature adipocytes and preadipocytes express a wide variety of functional toll-like receptors (TLRs) that respond to specific stimuli by producing cytokines, such as IL-6 [52, 53]. Furthermore, as inflammatory stimuli, TNF-α and IL-6 itself also promote IL-6 production in vitro [54]. Adiponectin, the anti-inflammatory adipokine, can inhibit IL-6 production accompanied by induction of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist [55]. C1q/tumor necrosis factor-alpha-related protein-3 (CTRP-3), regarded as another new potent anti-inflammatory adipokine, secreted by the adipose tissue can also reduce LPS-induced IL-6 and TNF-α secretion from monocytic cells by suppressing NF-κB signaling [56].

Effects of hormones

Besides inflammatory stimuli and stress, hormones appear to have an effect on IL-6 production. While estrogen inhibits IL-6 production in mice [57], estradiol replacement therapy does not alter IL-6 levels in postmenopausal women [58]. Moreover the published IL-6 levels in healthy women and men are also variable. Chan et al. [30] found higher IL-6 serum levels in men (3.31 vs. 2.10 pg/ml), but Giraldo et al. [59] measured higher values in women (2.84 vs. 2.26). Interestingly, their values differ more among males, most likely meaning that the differences were not due to the different timing of sample collection in females, but rather, that there is no alteration in the circulating IL-6 during the menstrual cycle [60], making the role of sexual hormones questionable. This discrepancy may be an appropriate topic to be further discussed in another review paper.

In addition to sex steroids, insulin infusion in humans can stimulate IL-6 gene expression in adipose tissue [61]. Further IL-6 release from cultured human adipocytes can be inhibited by glucocorticoids and induced by catecholamines [62]. In obese patients, all of these effects (stress, hormones, hypoxia, inflammation) can act simultaneously, and in every individual case, the microenvironment and the interaction of these factors can affect the outcome of IL-6 production (Fig. 1).
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Fig. 1

Regulation of IL-6 production. In obesity, cells of adipose tissue are the main source of IL-6 production. This productivity is strictly regulated by other adipokines and processes in adipose tissue such as leptin or stress and by hormones including insulin, catecholamines, and glucocorticoids

Effect of diet and exercise

It is well known that diet and exercise, when combined, are optimal therapies for obesity. Both have been suggested to have an effect on IL-6 serum level, but the results of experiments regarding exercise are controversial.

Serum concentrations of IL-6, TNF-α, and leptin are significantly correlated with BMI and fasting plasma insulin level. Bastard et al. [35] showed that IL-6 concentrations correlated significantly with fasting plasma glucose levels in diabetic and nondiabetic obese women and healthy lean women. Adipose tissue IL-6 content decreased significantly after a very low-calorie diet and was associated with a slight decrease in serum IL-6 concentrations. However, none of the observed modifications in IL-6 expression were directly associated with the loss in weight or in fat mass. Regarding short-term effects, hypoglycemia (glucose infusion to achieve steady-state plasma glucose concentrations) induces an acute elevation of plasma IL-6. In patients with impaired glucose tolerance, the IL-6 level was higher than in the healthy (but insulin secretion blocked) controls and the increased plasma level lasted longer [63].

Oberbach et al. [64] found that, despite a significant decrease in percent body fat and increase in insulin sensitivity, IL-6 plasma concentrations were unchanged after 4 weeks of physical training. Nicklas et al. [65] recently showed that exercise training did not have a significant effect on CRP (C-reactive protein) and IL-6 plasma concentrations, whereas diet-induced weight loss significantly improved these parameters of chronic inflammation. This discrepancy in results could be explained by the fact that IL-6 is typically the first cytokine present in the circulation during exercise, and plasma IL-6 increases in an exponential manner. IL-6 is released from skeletal muscle during exercise and is related to exercise intensity [66]. Subcutaneous adipose tissue, on the other hand, does not contribute to IL-6 secretion during exercise, so the increased output of IL-6 reported in the recovery phase following prolonged exercise is most probably from the skeletal muscle [67].

Unfortunately, the long-term consequence of regular exercise training on these inflammatory markers is unclear. A problem in the interpretation of data obtained by measuring release of factors by adipose tissue and fractions derived from adipose tissue is possibly because manipulation of the tissue may alter the rate of adipokine release.

Effect of bariatric surgery on IL-6 production

The most effective method for producing weight loss in patients with severe obesity (BMI >40 kg/m2) is bariatric surgery. Early publications showed that surgery did not have an effect on IL-6 production [68], however recent data show a relationship between weight loss after surgery and IL-6 concentration. Swabrick et al. [69] found IL-6 plasma levels were unchanged 1 month after laparoscopic roux-en-y gastric bypass surgery (RYGBP) but were reduced by 43 ± 7% at 12 months (P < 0.001). In other publication, IL-6 levels were also unchanged at 1 month after RYGBP, but similarly decreased by 6 months after weight loss intervention [70]. Kopp et al. [71] and Vazquez et al. [72] have shown similar attenuated IL-6 concentration 14 or 4 months after gastroplastic surgery in morbidly obese individuals. Since extensive weight loss inevitably follows bariatric procedures, these data support the relationship between adiposity and circulating IL-6 levels.

Effect of IL-6 in adipocyte function and obesity

IL-6 is a pleiotropic cytokine, acting as a central player in the regulation of inflammation, haematopoiesis, immune responses, and host defense mechanisms [73]. IL-6 has been classified as a pro- and anti-inflammatory cytokine [8]. This contradictory phenomenon also appears when examining the role of IL-6 in obesity.

Several reports suggest lipolytic properties of IL-6 [8, 74, 75]. Adipose tissue and adipocytes cultured with IL-6 show increased lipolysis [75, 76]. In agreement with this effect, Van Hall et al. showed IL-6/sIL-6R double transgenic mice had reduced body weight [77]. However, IL-6 deficiency led to mature-onset obesity in experiments of Wallenius et al. At 3 months of age, the IL-6 KO mouse was not obese, whereas by 9 months of age, it was obese, hypertriglyceridemic, and glucose intolerant, which by definition gives it a diagnosis of the metabolic syndrome [8]. The phenotype of the obese IL-6 knockout mouse was not observed in other studies [78]. The reason for the contradictory results obtained with IL-6-deficient mice in the previous two studies is unclear. The feeding protocols and the wild-type mice used as controls were slightly different, but in both cases the IL-6-deficient mice were studied on a C57BL/6 background.

IL-6 can influence the secretion of adipokines from adipocytes. Long-term IL-6/sIL-6R treatment gradually suppresses total adiponectin release from human adipocytes. IL-6 alone is unable to influence adiponectin synthesis, and the presence of sIL-6R is necessary in order to demonstrate IL-6 bioactivity in human adipocytes. This was demonstrated in another study [79] using human adipocytes: adiponectin gene expression was reduced by the IL-6/sIL-6R combination within 48 h, where IL-6 became ineffective. It was also demonstrated that long-term exposure to IL-6/sIL-6R suppresses total adiponectin secretion from delipidizing adipocytes without affecting the relative distribution of secreted adiponectin isoforms [80]. This finding suggests that adipocytes do not express IL-6Rα (ligand-binding subunit), but the expression of gp130 (signal transduction subunit) was confirmed [81].

Effect of human IL-6 and IL-6 receptor antibodies

In human clinical trials, the effect of recombinant human IL-6 antibody (Ab) or IL-6 receptor antibody treatment effect is usually anticachectic.

In cancer studies, where BE-8 anti-IL-6 monoclonal Ab was administered to acquired immunodeficiency syndrome patients at an advanced stage of HIV infection and suffering from an immunoblast-containing lymphoma, the anti-IL-6 monoclonal antibody had an anti-cachectic effect [82]. However in another study, when recombinant hIL-6 was administered to breast cancer or non-small-cell lung cancer patients, no effect on body weight was observed [83]. This discrepancy can be due to the contradictory effect of IL-6 on tumors. A direct and indirect anti-tumor capacity was demonstrated in vitro by growth inhibition of breast carcinoma and leukemia cell lines [84], but other studies showed IL-6 to support the growth of plasmocytoma, for example [85].

Another explanation of the preferentially anti-cachectic effect of IL-6 in cancer diseases could be the difference in IL-6 plasma level in patients, because in obese patients, the levels of IL-6 are slightly elevated, but near the normal level, whereas tumor expression is associated with a dramatic increase in IL-6 levels [86].

Studies with anti-IL-6 receptor antibodies (MRA and toclizumab) provide much more coherent data. Anti-IL-6 antibody receptor (MRA) is anti-cachectic in Castleman disease. Castleman disease is a rare, atypical lymphoproliferative disorder. Dysregulated overproduction of IL-6 from germinal center B cells is implicated in the pathogenesis of plasma-cell–type Castleman disease. Patients were treated with 8 mg/kg MRA every 2 weeks for 16 weeks. Nutritional status demonstrated by total cholesterol, high-density lipoprotein (HDL)–cholesterol, triglycerides, body weight, and body mass index (BMI) improved significantly in all patients during treatment with MRA [87]. In another anti-IL-6 receptor (MRA) study treating arthritis, a change in body weight was not measured, but abnormalities were observed for the laboratory profiles in 41, 57, and 76% of patients in the placebo, 4 mg, and 8 mg MRA/kg groups, respectively. Lipid metabolism-related reactions such as increases in total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were common in the MRA groups. A blood cholesterol increase was observed in 48 of 109 patients (44.0%) in the MRA groups [88]. This finding is concordant with a previous report that administration of recombinant IL-6 decreased serum cholesterol in cancer patients [83].

Plasma lipid levels (total cholesterol, LDL) also increased upon treatment with tocilizumab (at a dose of 8 mg/kg) in an other study (TOWARD, Tocilizumab in combination with traditional DMARD therapy) where patients suffering from rheumatoid arthritis were treated with humanized anti-IL-6 receptor monoclonal antibody [89].

Despite discrepancies regarding the effect of IL-6 in some rodent, tissue culture, and human experiments, we may conclude that both total lack and overabundance of IL-6 are detrimental in the control of body weight. Increasing data show that IL-6 has a significant role in the etiology of obesity-related co-morbidities including insulin resistance and accelerated atherosclerosis in humans [8] (Fig. 2).
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Fig. 2

Effect of IL-6. IL-6 plays a key role in the development of insulin resistance and atherosclerosis through a regulation of different mechanisms, including metabolic processes and endothelial dysfunction

Insulin resistance

Insulin resistance is characterized by the impaired action of insulin in organs sensitive to its effects, such as liver, muscle, adipose tissue, and the endothelium. While diabetes is the most obvious outcome of insulin resistance, its frequent association with hypertension, hyperlipidemia, and atherosclerosis has been referred to as the metabolic syndrome [90]. The association of obesity with type 2 diabetes has been recognized for decades, suggesting a causal link between obesity and insulin resistance. Chronic inflammation, indicated by persistently elevated serum and tissue levels of pro-inflammatory cytokines, is present in both conditions. In fact, inflammatory markers in obesity are considered predictors for developing type 2 diabetes and its associated co-morbidities [91]. Accordingly, circulating IL-6 levels are two- to threefold higher in obese type 2 diabetics than in nonobese controls [29, 38]. An association study in Pima Indians shows that fasting plasma IL-6 concentrations were positively related to adiposity and negatively related to insulin action but were not related to insulin secretion. The plasma IL-6 concentrations are inversely related to the rate of insulin-stimulated glucose disposal (M). However, after adjustment for obesity, M-low (low-dose insulin infusion) was not related to plasma IL-6 concentrations. The lack of a statistically significant association between M-low and plasma IL-6 concentration after adjusting for obesity is most likely due to the fact that adipose tissue secretes IL-6 or other factors that affect insulin action [15]. The other factor mentioned may be IL-1 because a combined elevation of IL-1β and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes [92].

Experiments have demonstrated that IL-6 can reduce insulin-dependent hepatic glycogen synthesis [93, 94] and glucose uptake in adipocytes [95]. Moreover in rodents, IL-6 injections lead to increased plasma glucose and insulin levels and a marked decrease in liver glycogen after 90 min [96]. Peripheral administration of IL-6, that mimics the levels present in obesity, has been shown to induce hyperlipidemia, hyperglycemia, and insulin resistance (as determined by impaired insulin receptor signal transduction) in both rodents and humans [97].

The intricate mechanism of cytokine-induced insulin resistance has not been clearly defined, but there are several hypotheses. One possible mechanism is the serine phosphorylation of insulin receptor substrate 1 (IRS-1) by cytokine-activated kinases and the subsequent direct inhibitory effect on the insulin-signaling cascade [98]. In fact, when HepG2 hepatoma cells and primary mouse hepatocytes were treated with IL-6, insulin signaling was inhibited at the level of insulin-dependent IRS-1 tyrosine phosphorylation, phosphatidylinositol 3-kinase association with IRS-1, and AKT/protein kinase B activation. Insulin-dependent glycogen synthesis was also markedly impaired in primary hepatocytes pretreated with IL-6. Furthermore, acute and chronic in vivo IL-6 exposure inhibited hepatic insulin sensitivity [94]. On the other hand, IL-6 has been shown to inhibit lipoprotein lipase and stimulate lipolysis. This lipolytic property of IL-6 may indirectly induce insulin resistance [74]. An alternative mechanism may be the cytokine-induced expression of cellular proteins, such as members of the suppressor-of-cytokine-signaling (SOCS) family, which inhibit insulin receptor signal transduction [99]. The latest experiments show that JNK1 deficiency in adipose tissue causes increased hepatic insulin sensitivity and this sensitivity is, at least in part, mediated by a requirement of JNK1 for HFD-induced expression of IL-6 [100]. Regardless of the precise mechanism, plasma IL-6 concentrations in combination with other factors can be used as a good predictor for the development of T2D [15, 92].

Atherosclerosis

As mentioned before, IL-6 has a significant role in the obesity-related co-morbidities including atherosclerosis in humans. IL-6 may play a key role in the development of atherosclerosis through a number of different mechanisms, including metabolic, endothelial dysfunction. Insulin resistance and adaptive hyperinsulinemia are thought to cause endothelial dysfunction and exert mitogenic influences on vascular smooth-muscle cells. This is in contrast to normal physiological conditions when insulin exerts a vasodilator effect achieved by promoting NO release [101]. Impaired insulin action in the adipose tissue leads to elevated rates of lipolysis, hence increased free fatty acid (FFA) release [102]. With regards to the vascular system, an increase in FFA impairs vasodilatation and reduces NO bioavailability by decreasing endothelial NO synthase activity and stimulates the production of reactive oxygen species by NADPH oxidase [103]. Hyperglycemia alone can induce endothelial free-radical production, increase the nonenzymatic oxidation of lipoproteins and superoxide concentration in endothelial cells, and augment the expression of adipokines, further fueling the vicious cycle of endothelial dysfunction [104]. These are all important changes to consider since atherosclerosis is an inflammatory process that initially begins with endothelial dysfunction [105].

Conclusion

The paradoxical role of IL-6 as a cachectogenic factor and a potential mediator of obesity may be resolved by the suggestion that a low level of inflammation is present in obesity and high levels of inflammation result in a loss of appetite [7, 8]. In other words, IL-6 as a paracrine factor is involved in the etiology of obesity, but IL-6 as an endocrine mediator acting on the hypothalamus is responsible for the loss of appetite during acute or chronic inflammation. The other possible resolution of the aforementioned controversy is that IL-6 is cachectogenic at the hypothalamic level, but it is involved in the induction of insulin resistance and dyslipidemia at the cellular level [106]. Insulin resistance is an age-related phenomenon, with a decline in insulin sensitivity beginning around middle age and progressively increasing. In mouse adipose tissue, insulin resistance and increasing age result in a higher expression of inflammatory mediators, including IL-6 [18]. In a recent large-scale human study, the positive correlation between inflammatory mediators and diabetes risk was not confirmed, signifying the need for further large-scale human trials [107].

Obesity is a complex, multifactorial trait that can not be explained by one factor, but IL-6 must be one of the contributing mediators. Despite the controversy, IL-6 is regarded at least as a modifier of obesity, and understanding and clarifying its exact role in the compound regulation of energy homeostasis and body-weight regulation may help in the planning of therapy and prevention of obesity—a socioeconomic challenge of the century.

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© Birkhäuser Verlag, Basel/Switzerland 2009