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What is the role of Interleukin-6 in Intermediary Energy Metabolism in Skeletal Muscle?Edit

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Figure 1: Human Intermediary Metabolism. A series of interconnected pathways having to do with sustaining life in all organisms. To better view the picture, click view full image at the top right of the thumbnail and zoom in.

Intermediary energy metabolism (IEM) refers to all the interconnected chemical reactions that occur with the that occur within the cells of living organisms that sustain life (Figure 1). While there are many pathways, perhaps the best known are those of glucose metabolism and fat metabolism in energy production (12). Due to the complexity of metabolism and the dynamic nature of a cell, there exists a need for regulation (4). Interleukin-6 is an inflammatory cytokine believed to be one such regulator of metabolism, albeit in an indirect manner (5). 

In this wiki, we provide a pathway in which IL6  stimulates fat oxidation (FAO) and glucose uptake/metabolism (GUM) via AMP activated protein kinase (AMPK) activation (5). AMPK is known as a central regulator of intermediary metabolism and is stimulated by an intracellular signalling pathway when the Interleukin-6 receptor is activated (IL6R) (5). With that being said, the impact that IL6 has on IEM is currently in contention (5). We provide strong evidence for IL6's role in indirectly contributing to IEM through AMPK. This wiki also describes the relationship between a cytokine released during the inflammatory response pathway and the metabolic disorders of diabetes and obesity. 

Interleukin-6 is an Inflammatory Cytokine Secreted During the Inflammatory Response Edit

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Figure 2: The role of IL6 in the inflammatory response pathway. IL6 is thought to 1. bind the IL6R which 2. recruits monocytes and 3. stimulate neutrophilic apoptosis and phagocytosis.

Interleukin 6 is an inflammatory cytokine thought to play a role in the inflammatory response (5).  Cytokines are cell signalling molecules involved in the process of intercellular communication (11). They are differentiated from hormones, which normally have very specific, localized effects and origin, by their ability to be produced by nearly all cells (particularly macrophages, skeletal muscle tissue, endothelial and epithelial cells) and and to induce potent, systemic responses (11). IL6's inflammatory response is thought to occur through monocyte recruitment and nucleophilic apoptosis and phagocytosis in the inflamed area (Figure 2) (13). IL6 signals the IL6R which induces an intracellular response  when an infection or abnormal cells are detected (11). IEM is ubiqituous throughout all cells of organisms (12). We focus on linking the immune system's IL6 cytokine to regulation of IEM through adenosine monophosphate-activated protein kinase or AMPK. Particularly in skeletal muscle, IL6 is shown to play a role in GUM and FAO (5). Key enzymes like AMPK and glucose transporter 4 (GLUT4) are upregulated by IL6 (5).

Interleukin-6 Binds to the IL6 Receptor and Activates Intracellular Signalling and AMPKEdit

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Figure 3: IL6 Signalling and the Receptor Complex. a. Cytokine signalling of IL6, IL6 binds to IL6R and associates with two gp130 molecules and induces signal transduction. b. The three dimensional strcture of the IL6 complex (dark blue, pink) with two receptors (light blue, grey) and two gp130 molecules (green, yellow)

IL6 plays an important role in the immune response pathway, leading to the inflammatory response in humans (110. While IL6 concentration has been linked to aberrant metabolism and even cancer, it has been shown in recent literature the effects of the IL6 pathway are highly divergent and this may have to do with intra-study variance/design rather than IL6's properties (5). Nevertheless, the pathway in which IL6 signals AMPK dependent IEM regulation is well characterized. The homodimeric IL6R recruits two gp130 molecules when IL6 binds to it (Figure 3) (11). This simultaneous binding activates intracellular signalling which activates AMPK which stimulates FAO and GUM (5). 

Interleukin-6 Stimulates AMP-activated Protein Kinase Edit

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Figure 4: AMPK deficient cells decrease the IL6 mediated glucose uptake. Ad null cells are regular control cells and Ad AMPK DN are AMPK dominant-negative-infected cells. Glucose uptake was measured in samples that were treated with nothing or insulin and/or IL6.

The majority of IL6's activities are directed through AMPK, an enzyme which maintains and regulates cellular energy (5). It maintains cellular energy by regulating processes such as lipolysis, lipogenesis and insulin secretion. A study performed by Andrew L. Carey et al. compares the dependency of IL6 on AMPK (5). Glucose uptake was looked at for two cell types induced with insulin and/or IL6. These cell types were ad Null which is a control and Ad AMPK AD cells which were AMPK dominant-negative-infected cells which are deficient in AMPK. A greater increase in glucose uptake was observed when cells were treated with insulin, IL6 or both, than the AMPK deficient cells (Figure 4)(5). 

IL6/AMPK is a Central Regulator of Glucose and Fat Metabolism Edit

To determine the role of IL6 on skeletal muscle IEM, studies characterizing IL6 signalling pathways were performed (5). The basis for this study was a previous finding that IL6 is upregulated during exercise and is hypothesized to be a factor in integrating metabolic response between multiple organs (5). In fact, exercise-released IL6 is positively correlated with skeletal muscle glucose uptake during contraction (5). The effects of acute and long-term IL6 dosage was measured in primary human muscle tissue on GUM were measured (5). IL6 increases both basal levels of GUM and has additive effects with insulin (Figure 8b) (5). Figure 8a shows that IL6 increases glycogen synthesis 1.5 fold, with no dosage effects (5).  

FA for IL-6

Figure 5: Effects of control, low and high dose of recombinant IL6 on FA metabolism. A. depicts the change of FA in arteries whereas B. shows the change in FA appearance/disappearance ratio. (6)

A study by Gerrit van Hall looked at the relation of fatty acid (FA) levels in comparison to recombinant IL6. FA was discovered to increase in the plasma (Figure 5)(6). The control had a stable level of FA in the plasma whereas the FA in IL6 induced samples experienced increases in FA levels. This suggests that IL6 does indeed increase lipolysis making it a possible novel lipolytic factor (6).

Hall's study examined the effects of high and low IL6 concentration on FAO. The study found that both concentrations resulted in similar FA production levels (Figure 5), however high levels of IL6 addition resulted in some immune response symptoms such as slight shivering and discomfort (6). These results in conjunction to a study done by Stouthard et al, find that overloading IL6 does not further stimulate lipolysis (6). In Stouthard's study, higher amounts of IL6 than Gerrit van Hall's study were administered on patients with metastatic renal cell cancer. The FA levels however were suprisingly similar to that of Gerrit van Hall's subjects leading to the conclusion that any concentration of above 140 pg/ml of IL-6 has the same effect on FA levels (6).

Hall found that IL6 does not directly affect FA lipolysis (6). FA levels spiked around 2.5 hours follwing infusion of IL6. FA levels also normalized after 3 hours after cessation of infusion. This sugges that IL6 is involved in an indirect pathway to increase lipolysis. This indirect pathway has IL6 affecting other molecules which directly affect the oxidation of FA (6). 

Looking at Figure 4, glucose transport is indeed upregulated by the addition of IL6. This process does occur through the regulation of AMPK by IL6 (5). The key change to upregulate glucose transport is through the translocation of GLUT4 from intracellular pools to plasma membrane which is directly stimulated by AMPK (5). GLUT4 is a trans-membrane protein that imports glucose from the bloodstream into cells. By bringing glucose into the cell, glucose concentration goes up in the cell and glycolysis will consequently increase. Glycolysis will produce pyruvate molecules from glucose which is converted into acetyl chains. These acetyl chains enter the Kreb's cycle and into the electron transport chain. 

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Figure 6: IL6 increases GLUT4 translocation in an AMPK dependent process. Activation of the IL6R pathway leads to increased GLUT4 translocation and therefore increased glucose uptake in skeletal muscle tissue. The IL6R pathway is insulin independent (though it has additive effects in increasing GLUT4 translocation with insulin) and instead involves serine/threonine kinase (LKB1) activating AMPK which activates the AS160 (Akt substrate of 160 kDa) protein that regulates GLUT4 translocation.

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Figure 8: IL6 increases rate of glycogen synthesis from glucose and has additive effects with insulin mediated glycogen synthesis. A. Dose response of acute (3h) treatment on varying concentrations (0, 5, 25, 100 ng/ml) of IL6 in differentiated primary human skeletal muscle myotubes. B. Insulin stimulated glucose incorporation into glycogen after 3h of treatment with 25 ng/mL IL6.

Interleukin-6 Receptor is a Potential Target for Type II Diabetes and ObesityEdit

Diabetes is a disease caused by abnormalities in the glucose metabolism pathway (7). Individuals with diabetes have extremely high levels of blood glucose levels, also known as hyperglycemia (3). Food consumed is converted to glucose which is then transported from the bloodstream into adipose and muscle cells. In type II diabetes patients the transportation of glucose into fat and muscle cells is difficult due to insulin resistance (7).  The lack of insulin binding is deterimental as insulin plays a major factor in glucose intake.Insulin very closely directs GLUT4 to join the plasma membrane (7). </span>

The pathogenesis of type II diabetes is hypothesized to be linked to a state of chronic inflammation (5). During this state, inflammatory cytokines are secreted and elevated levels of these cytokines in tissue have a negative effect on metabolism (5). Surprisingly, IL6 which was previously thought to have had a negative effect on insulin sensitivity due to experiments with mice, has shown to actually increase glucose uptake and GLUT4 translocation in humans (5). In the current literature, IL6 is hypothesized to induce GLUT4 translocation in a different pathway than insulin, relying on adenosine monophosphate-activated protein kinase (AMPK) instead to induce glucose uptake by skeletal muscle (Figure 6) (5).

Therefore, IL6 shows promise as a novel treatment for diabetes by overcoming insulin resistance to translocate the insulin sensitive GLUT4 onto the cell surface where it regulates glucose uptake into cells (Figure 7)(7).

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Figure 7: IL6 increases GLUT4 translocation similar to insulin.[2] In L6 myotubes, IL6 is shown to increase GLUT4 translocation. 100 ng/ml doses of IL6 and 100 nmol/l of insulin were used. Insulin dosage is represented with a white circle and IL6 dosage with a black square.

This effect is also unique to only certain tissues, notably skeletal muscle and adipose tissue.(5) Therefore, future therapy of diabetes could involve targeting the IL6R in muscle cells to treat peripheral insulin resistance in diabetes. Agonizing the IL6 receptor in muscle tissue should activate AMPK dependent GLUT4 translocation and increase glucose uptake in skeletal muscle.(5) Skeletal muscle is a viable target because 75% of whole-body insulin-stimulated glucose uptake occurs in skeletal muscle which is impaired in diabetes.(5).

Obesity has traditionally been associated with the increasing prevalence of diabetes (7). Obesity is defined as an excessive accumulation of fat such that the health of the individual is impaired and is very commonly co-morbid with diabetes (8). However, there are also benefits to weight-loss in diabetes patients (8). One study found that 90% of obese (BMI over 40) patients who achieved an average of 50 kg in weight-loss achieved normalization of their blood glucose levels (8). In addition, weight-loss has been associated with reductions in blood pressure and insulin resistance (7). The increased activation of AMPK in the IL6 pathway, which also increases fatty acid oxidation, has an additional advantage in diabetes treatment (5). This is because in adipocytes, AMPK is known to phosphorylate/inhibit ACC, which decreases malonyl CoA content, relieving inhibition of CPT-1 and increasing fatty acid oxidation (5). Therefore, an IL6R agonist should markedly enhance fatty acid oxidation via AMPK activation, leading to weight-loss and the benefits to diabetes treatment associated with it (7).

ReferencesEdit

1.   Abel, ED; Peroni, O; Kim, JK; Kim, YB; Boss, O; Hadro, E; Minnemann, T; Shulman, GI; Kahn, BB. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature, 2000, 409: 729-733

2. Stenbit, EB; Tsao, TS; Li, J, Burcelin, R; Geenen, DL; Factor, SM; Houseknecht, K; Katz, EB; Charron, MJ. Glut4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nat med. 1997, 10: 1096-101

3.  Sarwar, N; Gao, P; Seshasai, SR; Gobin, R; Kaptoge, S; Di Angelantonio, E; Ingelsson, E; Lawlor, DA; Selvin, E; Stampfer, M; Stehouwer, CD; Lewington, S; Pennells, L; Thompson, A; Sattar, N; White, IR; Ray, KK; Danesh,  J. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010, 375(9733): 2215-22

4. Mcauley, DF; Nugent, AG, McGurk, C; Maguire, S; Hayes, JR; Johnston, GD. Vasoconstriction to endogenous endothelin-1 is impaired in patients with Type ll diabetes mellitus. Clinical Science. 2000. 99: 175-179

5. Carey, AL; Steinberg, GR; Macaulay, SL; Thomas, WG; Holmes, AG; Ramm, G; Prelovsek, O; Hohnen-Behrens, C; Watt, MJ; James, DE; Kemp, BE; Pedersen, BK; Febbraio, MA. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-Activated Protein Kinase. Diabetes. 2006. 40: 2688-2697

6. Hall, GV; Steensberg, A; Sacchetti, M; Frischer, C; Keller, C; Schjerling, P; Hiscock, N; Moller, K; Saltin, B; Febbraio, MA; Pedersen, BK. Interlukin-6 stimulates lipolysis and fat oxidation in humans. JCEM. 2003. 88(7):3005-3010

7. Febbraio, MA; Rose-John, S; Pedersen, BK. Is Interleukin-6 Receptor Blockade the Holy Grail for Inflammatory Diseases? Clinical Pharmacology & Therapeutics, 2010, 87 4, 396–398.

8. Leong, KS; Wilding, JP. Obesity and diabetes. Bailliere's Clinical Endocrinology and Metabolism, 1999, 13(2):221-237.

9. Khalifi, L; Bouzraki, K; Glund, S; Lonnqvuist, F; Koistinen, H, Krook, A. Signaling Specificity of Interleukin-6 Action on Glucose and Lipid Metabolism in Skeletal Muscle. Mol. Endo2006, 20(12):3364-3375. 

10. Dinarello, C. Historical Insight into Cytokines. Eur. J. Immunol. 2007, 37:34-45. 

11. Boulanger, MJ; Chow, D; Brevnova, EE; Garcia, KC. Hexameric structure and assembly of the interluekin-6/IL-6 a-receptor/gp130 complex. Science, 2003, 2101-2104.

12. Macdonald, M. Biochem 3D03 Lecture Slides, Accessed 12/01/2013.

13. Gabay, C. Interleukin-6 and chronic inflammation.Arthritis Res Ther., 2006, 8 Suppl 2:S3 


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