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POINT-COUNTERPOINT
The Centre of Inflammation and Metabolism
Department of Infectious Diseases
Copenhagen Muscle Research Centre, Rigshospitalet
The Faculty of Health Sciences
University of Copenhagen
Copenhagen, Denmark
e-mail: bkp{at}rh.dk
Cellular and Molecular Metabolism Laboratory
Baker Heart Research Institute
Department of Biochemistry and Molecular Biology
Monash University
Melbourne, Australia
e-mail: mark.febbraio{at}baker.edu.au
POINT: INTERLEUKIN-6 DOES HAVE A BENEFICIAL ROLE IN INSULIN SENSITIVITY AND GLUCOSE HOMEOSTASIS
Growing evidence links Type 2 diabetes to a state of low-grade chronic inflammation, and it has been suggested that interleukin (IL)-6 promotes insulin resistance due to the observation that plasma IL-6 is often elevated in patients with metabolic disease. However, it is now well known that IL-6 is rapidly released into the circulation following exercise (8) and, from a simplistic physiological point of view, it seems paradoxical that working muscle would release a factor that inhibits insulin signaling when insulin action is enhanced in the immediate postexercise period (30). The idea of IL-6 being a bad guy with regard to metabolic actions is primarily based on 1) correlational relationships in cohort studies; 2) animal studies, neglecting that mouse and human IL-6 exhibit only 
42% sequence identity, and 3) in vitro cell culture studies of supraphysiological concentrations of IL-6. In this review, we challenge the generally held view that IL-6 is a bad guy based on recent carefully conducted experiments in both in vitro and, importantly, humans in vivo.
The in vivo effect of IL-6 on glucose and lipid metabolism. Although IL-6 appears to play a role in endogenous glucose production (EGP) during exercise in humans, its action on the liver is dependent on a yet unidentified muscle contraction-induced factor (7). In healthy humans in the basal condition, acute rhIL-6 administration at physiological concentrations does not impair whole body glucose disposal, net leg glucose uptake, nor does it increase endogenous glucose production (14, 17, 23). In patients with Type 2 diabetes, rhIL-6 decreases circulating insulin, suggesting an insulin-sensitizing effect of IL-6 (17). To test this hypothesis, we recently demonstrated that IL-6 increased glucose infusion rate and glucose oxidation without affecting the suppression of endogenous glucose production during a hyperinsulinemic euglycemic clamp in healthy humans (4). These data are in contrast with observations reported in mice (11). The finding of an insulin-sensitizing effect of IL-6 at conditions where EGP was completely suppressed underlines that in humans, the main effects of IL-6 with regard to glucose metabolism are likely to be in peripheral tissues (muscle, adipose), whereas IL-6 does not influence glucose output from the liver.
Infusion of rhIL-6 into healthy humans to obtain physiological concentrations of IL-6 increased lipolysis in the absence of hypertriacylglyceridemia or changes in catecholamines, glucagon, insulin, or any adverse effects in healthy individuals (14, 17, 25) and in patients with Type 2 diabetes (17). These findings, together with cell culture experiments demonstrating that IL-6 alone markedly increases both lipolysis and fat oxidation, identify IL-6 as a novel lipolytic factor (17). Interestingly, Axokine, a human variant of the IL-6 family cytokine member ciliary neurotrophic factor (CNTF), which acts via a common receptor with IL-6 (the IL-6R/LIFR/ CNTFR/gp130 receptor complex), induces marked weight loss in obese patients (6). Moreover, blocking IL-6 in clinical trials with patients with rheumatoid arthritis leads to enhanced cholesterol and plasma glucose levels, indicating that functional lack of IL-6 may lead to insulin resistance and an atherogenic lipid profile (1, 5, 15). In accordance, IL-6 knockout mice develop late onset obesity and impaired glucose tolerance (26). Together, these studies add weight to the notion that IL-6 family cytokines are "anti-obesogenic."
Mechanisms of action. In isolated hepatocytes and in mice in vivo, IL-6 has a negative effect on hepatic insulin sensitivity. These findings are without clinical relevance as in vivo studies in humans clearly demonstrate that neither splanchnic glucose output measured by a-v balance across the hepatosplanchnic tissue nor isotopic tracer determined endogenous glucose production is increased by acute infusion of rhIL-6 (14, 17, 23). In vitro, IL-6 either enhances (4, 24) or does not enhance (13, 20) glucose transport in adipocytes. The fact that IL-6 infusion increases subcutaneous adipose tissue glucose uptake in humans (14) argues against IL-6 as an insulin resistance-inducing agent in adipocytes. In addition, several studies reported that IL-6 increases intramyocellular or whole body fatty acid oxidation, which is likely to decrease intramyocellular fatty acid accumulation, which can impair insulin signaling (reviewed in Ref. 4). With regard to myocytes, IL-6 enhances insulin-stimulated glucose transport (4) and glycogen synthesis (28). In vivo, experiments demonstrated that IL-6 increases basal and insulin-stimulated glucose uptake via an increased GLUT4 translocation (4).
Recent evidence suggests a link between IL-6 and AMP-activated protein kinase (AMPK). AMPK activation stimulates fatty acid oxidation and increases glucose uptake (9). IL-6 was shown to enhance AMPK in both skeletal muscle and adipose tissue (10) and, more recently, the effects of IL-6 on enhanced glucose uptake in skeletal myotubes were abolished in cells infected with an AMPK-dominant negative construct (4). Studies have shown that IL-6 can enhance lipid oxidation in vitro (17), ex vivo (2), and in vivo (17, 25). AMPK phosphorylates ACC, resulting in inhibition of ACC activity, which in turn leads to a decrease in malonyl CoA content, relieving inhibition of CPT-1 and increasing fatty acid oxidation (9). We recently showed that the IL-6-mediated phosphorylation of ACC and subsequent palmitate oxidation is AMPK dependent (4). Our data, together with our recent findings regarding CNTF, which markedly enhances lipid oxidation via activation of AMPK (27), suggest that ligands that bind to the gp130 receptor complex can enhance glucose uptake and fat oxidation via activation of AMPK.
IL-6 has been shown to activate SOCS proteins in liver, leading to hepatic insulin resistance (21). IL-6 increased SOCS3 expression in myotubes, but concomitantly increased glucose uptake in these cells (4). While IL-6 increased SOCS3 twofold in muscle, it was increased 25-fold in liver, suggesting that capacity for IL-6 to induce SOCS3 is much greater in hepatic tissue (29). The possibility exists that the negative effects of IL-6 on SOCS3 may be overridden by the positive effects on AMPK.
IL-6 stimulates the production of anti-inflammatory cytokines (16) and suppresses TNF-
production in humans (22). Direct evidence for a role of TNF in insulin resistance in humans has been obtained (19) and it is likely that muscle-derived IL-6 offers protection against TNF-induced insulin resistance (16).
If IL-6 is a good guy, why does it coexist with the bad guys?
Subjects with risk genotypes for both TNF- (AA; A shows increased TNF transcription) and IL-6 (CC; C shows decreased transcription) have the highest incidence of diabetes (12), favoring the theory that high levels of TNF- and low production of IL-6 are determining factors in the metabolic syndrome. High circulating levels of IL-6 may or may not be found in patients with Type 2 diabetes, but in general IL-6 is not elevated in lean subjects with insulin resistance (3, 18). Given the different biological profiles of TNF- and IL-6 and given that TNF- can trigger IL-6 release, one theory holds that it is adipose tissue-derived TNF- that is actually the "driver" behind the metabolic syndrome and that increased systemic levels of IL-6 reflect locally produced TNF- (16). Although IL-6 increases and TNF- decreases insulin-stimulated glucose uptake in adipocytes, the addition of TNF- to IL-6 totally abolishes the enhanced insulin action, highlighting the notion that it is TNF, not IL-6, that is the "bad guy" (Hage M et al., unpublished observations).
In summary, acute IL-6 administration to humans increases insulin-stimulated glucose disposal and fatty acid oxidation in vivo and IL-6 has strong anti-inflammatory effects. Activation of AMPK by IL-6 appears to play an important role in modulating some of these metabolic effects.
GRANTS
Support was obtained from the Danish Medical Research Foundation, and the Commission of the European Communities (Contract No. LSHM-CT-2004–005272 EXGENESIS). Studies conducted by M. A. Febbraio were supported by grants from the National Health and Medical Research Council (NHMRC Project Grant Nos. 251558, 342115, 392206). M. A. Febbraio is a Senior Research Fellow of the NHMRC.
ACKNOWLEDGMENTS
We thank the Centre of Inflammation and Metabolism (supported by Danish National Research Foundation Grant DG 02–512-555) and the Copenhagen Muscle Research Centre (supported by grants from the University of Copenhagen, the Faculties of Science and of Health Sciences at this university, and the Copenhagen Hospital Corporation).
REFERENCES
Department of Pathology and Laboratory Medicine
University of Rochester Medical Center
Rochester, New York
Interleukin (IL)-6 is a pleiotropic cytokine with involvement in such diverse physiological and pathological functions as innate immunity and acute phase response, hematopoiesis, liver regeneration, and repair (1, 26). Evidence also supports a role for IL-6 in glucose metabolism and insulin action, but the nature of this role is controversial. As discussed by Dr. Pedersen and Dr. Febbraio, my Point:Counterpoint colleagues whose research has made major contributions to this field, IL-6 can display beneficial effects in regulating glucose metabolism, particularly in skeletal muscle (8). The important question as I see it, however, is whether IL-6, in pathological conditions, contributes to glucose dysregulation. Although IL-6 may have a benign or beneficial role under certain experimental conditions, I will argue that in its relationship to obesity and insulin resistance, which affects as many as one-third of adults in the United States, the contribution of IL-6 is decidedly detrimental, particularly in the liver.
Recent evidence indicates that obesity, with its associated insulin resistance and Type 2 diabetes, is a chronic inflammatory state (29). Considerable effort is directed at determining the contribution of the cytokines, adipokines, and related factors to the altered glucose homeostasis and insulin resistance of this inflammatory state. Circulating IL-6 levels are two- to fourfold higher in obese, Type 2 diabetics than in nonobese controls (7, 17, 18). Kern et. al (12) reported that plasma IL-6 levels correlate better than TNF- with obesity and insulin resistance. Similarly, Bastard et al. (3) reported that adipose tissue IL-6 levels but not TNF- or leptin levels correlate with insulin resistance in obese subjects. IL-6 levels in serum and adipose tissue also decrease with weight loss (2). A recent study demonstrated that levels of CRP and IL-6 correlate with both insulin resistance and obesity and predict the development of Type 2 diabetes (19). Adipose tissue makes an important contribution to circulating IL-6 levels (16), and the liver is a well- characterized target of IL-6. Omental fat is more strongly linked to insulin resistance than non-visceral fat depots (6) and secretes as much as two- to threefold more IL-6 than subcutaneous fat (9). Importantly, venous drainage of omental fat uses the portal venous system, hence potentially having a preferential effect on the liver.
Is IL-6 an active participant in the insulin resistance and altered carbohydrate metabolism of obesity or is this guilt by association? Both in vivo and in vitro evidence is available to address this question. Kanemaki et al. (11) and others (20) reported that IL-6 inhibits insulin-dependent glycogen synthesis and promotes glucose release from isolated primary hepatocytes. Our group has shown that IL-6 impairs insulin receptor signaling in HepG2 cells and primary hepatocytes and confirms that insulin-dependent glycogen synthesis is inhibited by IL-6 (23). Rotter et al. (21) reported that gene transcription of IRS-1, GLUT4, and PPAR-
decreased in response to chronic IL-6 in 3T3L1 adipocytes. Insulin-dependent glucose transport and IRS-1 tyrosine phosphorylation were also suppressed.
While in vitro investigations have shown direct inhibitory effects of IL-6 on insulin- responsive target cells, in vivo experiments also support such an effect of IL- 6. In rodents, IL-6 injections lead to increased plasma glucose and insulin levels after 90 min and a marked decrease in liver glycogen (25). Additionally, we reported that mice acutely exposed to IL-6 for 90 min have reduced insulin signal transduction in the liver (24). If the objective is to characterize the role of IL-6 in obesity, however, IL-6 levels should be maintained in a chronically elevated state to mimic obesity. To this end, we used implantable osmotic pumps that deliver IL-6 continuously to mice over 5–7 days. Under these conditions, IL-6 produced a hepatic insulin resistance as determined by impaired insulin receptor signal transduction. Interestingly, skeletal muscle response to insulin was unimpaired (15). Using a more acute IL-6 treatment, Kim et al. (13) infused IL-6 for 3 h during a hyperinsulinemic-euglycemic clamp study. Under these conditions, insulin resistance was observed in both the liver and skeletal muscle. Perhaps the latter reflects the higher dose used and the shorter time frame of the study.
To directly address the role of IL-6 in glucose dysregulation of obesity, an IL-6 neutralizing antibody was used to deplete IL-6 in genetically obese Lepob mice (14). Prior to antibody treatment, elevated STAT3 phosphorylation and increased expression of acute phase proteins haptoglobin and fibrinogen were observed in liver and adipose tissue of the obese mice compared with lean controls, consistent with an obesity-associated elevation of endogenous IL-6. Neutralization of IL-6 returned these markers toward levels seen in lean mice. Importantly, insulin receptor signaling increased in the liver but not in adipose tissue in response to IL-6 depletion. Of relevance to our current discussion, depletion of IL-6 increased insulin sensitivity in the obese mice as reflected in a marked improvement in insulin-dependent suppression of endogenous glucose production (14). Cai et al. (4) reported a similar increase in hepatic insulin sensitivity following treatment of a transgenic mouse model of insulin resistance with IL-6 neutralizing antibody. They argue further that the liver can be an important source of IL-6, with steatosis being a potent stimulus for increased production.
Is IL-6 a promoter of insulin sensitivity and glucose utilization as suggested in part by the expertly performed, acute, human studies by Drs. Pedersen, Febbraio, and colleagues, or is IL-6 the antagonist of insulin action as argued in the studies outlined here? What factors may account for the apparent contradictory effects of IL-6 on glucose homeostasis? Chronicity may be one factor. Most human investigations are by necessity limited to several hours. Obesity is a chronic condition, and the role of IL-6 in this condition may require chronic elevations. Chronic, but not acute, exposure to IL-6 causes inhibitory changes in insulin action in 3T3L1 adipocytes (21). Evidence from the liver regeneration field suggests that short-term (1–2 days) IL-6 exposure yields a protective effect, whereas long term (5–7 days) IL-6 exposure is injurious (10). Differences in response to IL-6 between the insulin responsive tissues are also a factor. While skeletal muscle appears to be the major target for the reported beneficial effects of IL-6, Weigert et al. (28) recently confirmed that, in the liver of mice, IL-6 activates two inhibitory mechanisms that are implicated in insulin resistance, marked induction of SOCS-3 and phosphorylation of IRS-1 on serine-307. Interestingly, IL-6 had no appreciable effect on these inhibitory mechanisms in skeletal muscle. Carey et al. (5) recently confirmed the small effect of IL-6 on SOCS-3 expression in muscle. This tissue-specific difference in induction of SOCS-3 may be quite relevant to this current discussion because we and others have linked SOCS-3 to inhibition of insulin receptor signal transduction in the liver (22, 24, 27). Finally, physiological context may play an important role in determining the response to an inflammatory cytokine such as IL-6. In 3T3L1 adipocytes, IL-6 alone had no acute effect and IL-1 had only a small inhibitory effect on insulin receptor signal transduction (28). Together, however, these two inflammatory cytokines very potently inhibited insulin receptor signaling. Thus, although considerable evidence supports a role for IL-6 in promoting insulin resistance and glucose dysregulation, optimum characterization of this role may require consideration of the synergy between IL-6 and other elements of the proinflammatory milieu.
GRANTS
The author recognizes support from the National Institute of Diabetes and Digestive and Kidney Diseases (Grants DK-38138 and DK-60732) and the American Diabetes Association (7–04-RA-78).
REFERENCES
and not IL-6 may indeed be the "sheep in wolf's clothing." In a recent study (9), plasma-IL-6 concentrations were markedly lowered by anti-TNF- therapy. This finding that plasma TNF- was not elevated despite high levels of IL-6 and that plasma-IL-6 levels decreased in response to anti-TNF- therapy supports the notion that TNF- may stimulate IL-6 production and consequently IL-1ra and CRP. In line with this, chronically elevated levels of IL-6 are likely to reflect local ongoing TNF- production, the real cause of cytokine-induced insulin resistance in humans. REFERENCES
are not elevated in patients with type two diabetes: evidence that plasma IL-6 is related to fat mass and not insulin responsiveness. Diabetologia 47: 1029–1037, 2004.[Web of Science][Medline] therapy. Scand J Rheumatol. In press.Without definitive human studies, an understanding of the effects of chronic IL-6 must come from animal and in vitro studies. Depletion of circulating IL-6 in obese mice improved hepatic insulin responsiveness but had no effect in lean mice (7). This supports the conclusion that IL-6 is an important mediator of obesity-associated insulin resistance and is more than the marker of obesity that my colleagues contend (3). This is further supported by Kern et al. (6) who demonstrated that circulating IL-6 levels correlate with insulin resistance independent of BMI.
Finally, tissue-specific differences in response to IL-6 may underlie the two faces of IL-6. My colleagues link IL-6-dependent activation of AMP kinase in L6 myotubes to beneficial metabolic effects of IL-6 in skeletal muscle (6). Interestingly, they had questioned in vitro approaches, particularly those using supraphysiological IL-6 concentrations, yet 100 ng/ml IL-6 was used in their study. We have shown IL-6- dependent inhibition of insulin signaling and increased expression of SOCS-3, a potential mediator of insulin resistance, in hepatocytes in response to fivefold less IL-6 (10). Additionally, IL-6 induces little SOCS-3 in myotubes and is not an effective activator of AMP kinase in liver (5). This supports the conclusion that the liver is a major site for IL-6-dependent dysregulation of insulin action while skeletal muscle may not be a target for this effect.
REFERENCES
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