IL-6: The “Other” Leptin

Advertise here

IL-6: The “Other” Leptin

Why taking in carbs during your workout is a good idea.

By Bill Willis PHDc and John Meadows CSCS, CISSN

Muscle contraction increases insulin sensitivity and fat burning not only in muscle tissue, but also all over the body. How this happens remained a mystery for years, until it was recently discovered that muscle also functions as an endocrine organ, producing a number of “myokines”, which are released into the circulation to influence metabolism. Think of myokines as special chemical messengers, sent from muscle tissue to co-ordinate metabolic changes all over the body in response to exercise. Myokines activate glucose disposal, potentiate the effects of insulin, and increase fat burning. A number of myokines have been discovered, but interleukin -6 (IL-6) in particular has emerged as one of the most important ones. With many leptin like properties, IL-6 can be considered the “leptin” of muscle tissue. Released in response to intense training, IL-6 increases insulin sensitivity and fat burning, while at the same time decreasing inflammation. Like leptin, IL-6 activity and release can be influenced by training and nutritional variables, so read on to learn more about this powerful myokine: what it does, how it works, and what we can do to harness its power.

Exercise, the immune system, and the discovery of myokines

For most of the last century, scientists have scratched their heads over the link between muscle contraction and exercise-induced metabolic changes. Because training a muscle hard causes metabolic changes all over the body, researchers reasoned that there must be some kind of “exercise factor” that is released in response to muscle contraction. This mystery “exercise factor” would then somehow communicate with other tissues, increasing insulin sensitivity and fat-burning all over the body. The problem is, the source of this exercise factor was completely unknown, let alone how it might work.

One clue as to the identity of this “exercise factor” was revealed when the connection between muscle and the immune system was discovered. Hard training activates the immune system, which is intimately involved in the muscle growth and repair process. The connection between muscle and the immune system remained a mystery for many years, until it was discovered that exercise changes the distribution and concentration of different types of the immune cells. Scientists knew at the time that hormones called “cytokines” regulated immune activity, so early work focused on cytokines as a possible link between muscle contractions and changes to the immune system. This work led to the discovery that exercise causes an increase in the number of cytokines in the blood stream, particularly IL-6 (1, 2). Because IL-6 is one of the “classical” inflammatory cytokines of the immune system, scientists initially reasoned that IL-6 was released by immune cells in response to muscle damage (3), possibly as part of an early inflammatory response. After all, IL-6 is produced by muscle fibres and accumulates during exercise (4, 5). It turned out that negative contractions, which are the most damaging type of contraction, didn’t increase IL-6 any more than “non-damaging” positive contractions, however. This ruled out the idea that muscle damage was the trigger for increased blood levels of IL-6 during exercise. In the year 2000 scientists discovered that intensely contracting skeletal muscle actually produces massive amounts of the cytokine IL-6, which is also released into the circulation (6). Finally, the mystery “exercise factor” was discovered, and the term “myokine” was born.

The split personality of IL-6

As the most potent myokine known to date, you might think it is slightly strange that the full potential of IL-6 has only recently come to light. The major reason for this is due to the fact that IL-6 has a dark side, leading to some initial disagreement over whether it is helpful, harmful, or something in-between. IL-6 activity is a bit of a paradox: On one hand, high IL-6 levels are associated with metabolic disease, insulin resistance, and obesity (7). Independent of these disease-states, IL-6 is linked to low levels of physical activity, so in that sense, it could also be considered the “out of shape” hormone. Because of this, IL-6 was previously thought to be an actual cause of insulin resistance. This belief was challenged by the discovery that IL-6 is a myokine, produced and released from skeletal muscle in response to hard work. We know that intense training increases insulin sensitivity (8), and insulin action is enhanced in the post-workout period (9). Why then, would muscle shoot itself in the foot by producing massive amounts of something that decreases insulin sensitivity? It turns out that IL-6 has a totally split personality. Chronically high IL-6 levels are associated with low levels of physical activity, insulin resistance, and obesity, in spite of the fact that IL-6 levels increase in the post-exercise period, where it enhances insulin action and fat burning.

So IL-6 has both negative and positive effects… but how does this work? It turns out that there is a big difference between acute and chronic IL-6. Acute IL-6 is good, chronic IL-6 is bad. When you are at rest, you want IL-6 to be as low as possible. Acute IL-6, released in response to intense training, enhances glucose uptake and fatty acid oxidation in skeletal muscle. Chronically elevated IL-6 causes IL-6 resistance, which is a driver of insulin resistance in those who are overweight, obese, and or generally out of shape (10). Likewise, there is a lot of evidence that IL-6 sensitivity improves with physical activity, causing baseline IL-6 levels to decrease. Cardio work in elderly adults has been shown to decrease resting IL-6 (11), and the combination of a low calorie diet and regular exercise also reduces resting plasma IL-6 in the severely obese. While resting IL-6 is reduced by training, expression of muscle IL-6 receptors actually increases up to 100% in response to regular exercise (12). The more IL-6 receptors you have, the more sensitive you will be to its effects. This is why resting IL-6 levels actually decrease when you are in good condition. The better shape you are in, the lower your IL-6 levels will be at rest (13-15).

Acute (good) and chronic (bad) IL-6 may also come from completely different sources. “Bad” IL-6, which drives insulin resistance, is released from adipose tissue and contributes more to chronically increased IL-6 at rest (16, 17). “Good” IL-6 is released from muscle tissue in response to hard training, where it increases insulin sensitivity and fat burning,

How does IL-6 work, and what does it do?

IL-6 activates pathways that burn fat, increase insulin sensitivity, and decrease inflammation. It acts as a “fuel gauge” for muscle tissue, where it is released when muscle glucose levels are low, causing an increase in glucose production in the liver while also increasing lipolysis during exercise (18, 19). IL-6 is responsible for much of the direct fat-burning effects from intense training, amplifying fat oxidation in intramuscular (20-22) and whole body fat stores (23). IL-6 also enhances insulin signaling by at least three different mechanisms. First, IL-6 plays a role in insulin-independent glucose uptake, which is activated by muscle contraction during exercise. When hard contracting muscle releases IL-6, this increases the amount of GLUT4 translocation to the muscle cell membrane, leading to increased glucose uptake (21). Second, IL-6 also enhances insulin-dependent glucose uptake by increasing insulin sensitivity and insulin release. This increases insulin-stimulated glucose uptake during and after exercise (24), leading to increased glucose disposal, protein synthesis, and much fuller muscles. Finally, IL-6 increases insulin sensitivity by suppressing chronic inflammation (25).

The role of IL-6 in insulin signaling can’t be understated. This has huge implications for hard training athletes; enhanced insulin action in the post-workout period doesn’t stop at better glucose disposal. You are more anabolic, as protein synthesis increases and protein degradation is suppressed. IL- 6 also prevents the fat burning machinery from being turned off during the insulin response. Under normal circumstances, elevated insulin levels flip a biochemical switch that turns off fat oxidation and lipolysis. With IL-6 in the picture, post-exercise insulin signaling is enhanced but fat burning actually increases, instead of being shut down. In doing this, IL-6 performs nothing short of metabolic magic because it hacks your metabolism to prevent the fat burning machinery from being shut down during the insulin response.

IL-6 and inflammation

While both chronic and low-level inflammation doesn’t put your health in immediate danger, it can wreak havoc over time. Low grade inflammation is a big cause of aging and is also the cause/effect of obesity, insulin resistance and diabetes (25). Chronic, low-grade inflammation causes a 2-3 time increase in the inflammatory cytokines TNFα, IL-1, CRP and others. TNFα induces insulin resistance by several different pathways, and it is a direct molecular link between low-grade systemic inflammation and insulin resistance (26). While acute TNFα is vital to the muscle repair process, we generally want to do whatever we can to keep TNF levels as low as possible at other times. This is where IL-6 comes in. Exercise is an inhibitor of chronic inflammation, and this happens by way of increased systemic levels of a number of anti-inflammatory cytokines, including IL-6 (27). As the first cytokine present in the circulation during exercise, IL-6 is a driver of the anti-inflammatory effects of training, which protects against both chronic and low grade inflammation. By suppressing chronic inflammation, exercise-induced IL-6 also increases insulin sensitivity.

The “leptin” of muscle tissue

The IL-6 signaling pathway has many similarities to leptin signaling. The major one is that both leptin and IL-6 both function as a sort of metabolic “fuel gauge”, but in different tissues. Leptin monitors whole-body energy levels to co-ordinate energy expenditure, fat oxidation and overall metabolism. IL-6 is the “fuel gauge” of muscle tissue, cranking up glucose disposal and increasing fat oxidation when muscle glycogen levels are low. IL-6 and leptin also operate through similar signaling pathways. In their role as metabolic “fuel gauges”, leptin and IL-6 both activate AMPK, (21, 28) a cellular energy sensor. AMPK activation is responsible for much of the fat burning effects of leptin and IL-6. Finally, as with leptin resistance, IL-6 resistance is associated with paradoxically high IL-6 levels, insulin resistance, inflammation, and obesity.

Three tips to Harness the power of IL-6

1. Train hard, and train consistently

Obviously hard, consistent training is a pre-requisite to get anywhere, but it turns out that IL-6 mediates many of the beneficial effects here. Type, intensity, and duration of exercise determine the amount of IL-6 release. The harder you train, the more IL-6 is released (29), and working larger muscle groups causes more IL-6 release than smaller muscle groups. Hard, consistent training also increases IL- 6 sensitivity, which decreases resting IL-6 levels (i.e. “bad” IL-6). Because of the relationship between IL-6 and exercise duration and intensity, higher volume training protocols may have a distinct advantage over lower-volume approaches when it comes to IL-6 release. Calcium drives muscle contraction, and mechanical load is a big factor in muscle calcium signaling. The IL-6 gene promoter is also calcium-responsive (30), so heavy loads with sufficient time under tension will tend to promote greater IL-6 release.

2. Avoid supplemental antioxidants

Research has demonstrated that IL-6 release in working muscles is blocked by antioxidants. Oral supplementation with vitamin C, E for 4 weeks almost completely prevented IL-6 release in working muscles (31). Try to get your antioxidants mostly from whole-food sources. If you are still convinced you need to take antioxidant supplements, avoid taking them around the times that you train.

3. Train low

There are many good reasons to have plenty of carbs around the peri-workout period. IL-6 release from muscle tissue is maximised, but only when muscle glycogen levels are low. This triggers the stress-response protein P38 MAPK, which turns on the IL-6 gene resulting in increased IL-6 production (25). It has also been demonstrated in a number of studies that glucose ingestion during training attenuates exercise-induced IL-6 release (17, 32-35). Glucose ingestion during exercise does not, however, stop IL-6 from being produced in the muscle; only from being released into the blood stream (35-37). While carbs during training may negate some of the overall fat burning effects of IL-6, the positive effects of IL-6 in muscle tissue (increased glucose disposal/insulin sensitivity) are not affected. Therefore, it is best to keep the carbs in the peri-workout period when you are in mass gaining phases of your training. For maximal fat loss phases, you can best take advantage of the fat-burning effects of IL-6 by training “low”. Fat-burning effects of IL-6 are maximised if you keep carbs on the low side before/during training.

Conclusion.

IL-6 co-ordinates the insulin-potentiating and fat-burning effects of exercise. Very “leptin-like” in character, IL-6 functions as a sort of muscle “fuel gauge”, also increases insulin sensitivity, lipolysis, and fat oxidation. In the fitness industry, truly “academic” knowledge is of little use without a practical application, so I listed a few tips to get the most out of IL-6. It is important to stress however, that our knowledge of IL-6 and other myokines is still evolving. IL-6 is a big part of the picture, but it is definitely not the whole picture. That said, the tips listed above are effective, practical, and based on the latest scientific research. Use them to take your training to the next level.

Reference List

1. Most MM, Tulley R, Morales S, Lefevre M. Rice bran oil, not fiber, lowers cholesterol in humans. Am J Clin Nutr 2005;81:64-8.

2. Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 2005;33:114-9.

3. Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA, Pedersen BK. Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage. J Physiol 1997;499 ( Pt 3):833-41.

4. Langberg H, Olesen JL, Gemmer C, Kjaer M. Substantial elevation of interleukin-6 concentration in peritendinous tissue, in contrast to muscle, following prolonged exercise in humans. J Physiol 2002;542:985-90.

5. Rosendal L, Sogaard K, Kjaer M, Sjogaard G, Langberg H, Kristiansen J. Increase in interstitial interleukin-6 of human skeletal muscle with repetitive low-force exercise. J Appl Physiol 2005;98:477-81.

6. Steensberg A, van HG, Osada T, Sacchetti M, Saltin B, Klarlund PB. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol 2000;529 Pt 1:237-42.

7. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 1999;19:972-8.

8. King DS, Dalsky GP, Clutter WE, Young DA, Staten MA, Cryer PE, et al. Effects of exercise and lack of exercise on insulin sensitivity and responsiveness. J Appl Physiol 1988;64:1942-6.

9. Wojtaszewski JF, Hansen BF, Gade, Kiens B, Markuns JF, Goodyear LJ, et al. Insulin signaling and insulin sensitivity after exercise in human skeletal muscle. Diabetes 2000;49:325-31.

10. Fischer CP, Berntsen A, Perstrup LB, Eskildsen P, Pedersen BK. Plasma levels of interleukin-6 and C-reactive protein are associated with physical inactivity independent of obesity. Scand J Med Sci Sports 2007;17:580-7.

11. Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 1994;265:956-9.

12. Keller C, Steensberg A, Hansen AK, Fischer CP, Plomgaard P, Pedersen BK. Effect of exercise, training, and glycogen availability on IL-6 receptor expression in human skeletal muscle. J Appl Physiol 2005;99:2075-9.

13. Cesari M, Penninx BW, Pahor M, Lauretani F, Corsi AM, Rhys WG, et al. Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 2004;59:242-8.

14. Colbert LH, Visser M, Simonsick EM, Tracy RP, Newman AB, Kritchevsky SB, et al. Physical activity, exercise, and inflammatory markers in older adults: findings from the Health, Aging and Body Composition Study. J Am Geriatr Soc 2004;52:1098-104.

15. Panagiotakos DB, Pitsavos C, Chrysohoou C, Kavouras S, Stefanadis C. The associations between leisure-time physical activity and inflammatory and coagulation markers related to cardiovascular disease: the ATTICA Study. Prev Med 2005;40:432-7.

16. Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab 1997;82:4196-200.

17. Nieman DC, Davis JM, Brown VA, Henson DA, Dumke CL, Utter AC, et al. Influence of carbohydrate ingestion on immune changes after 2 h of intensive resistance training. J Appl Physiol 2004;96:1292-8.

18. Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK, et al. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB J 2001;15:2748-50.

19. Steensberg A, Febbraio MA, Osada T, Schjerling P, van HG, Saltin B, et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol 2001;537:633-9.

20. Petersen EW, Carey AL, Sacchetti M, Steinberg GR, Macaulay SL, Febbraio MA, et al. Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro. Am J Physiol Endocrinol Metab 2005;288:E155-E162.

21. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG, Ramm G, et al. 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;55:2688-97.

22. Bruce CR, Dyck DJ. Cytokine regulation of skeletal muscle fatty acid metabolism: effect of interleukin-6 and tumor necrosis factor-alpha. Am J Physiol Endocrinol Metab 2004;287:E616-E621.

23. van HG, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 2003;88:3005-10.

24. Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 2011;17:1481-9.

25. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008;88:1379-406.

26. Plomgaard P, Bouzakri K, Krogh-Madsen R, Mittendorfer B, Zierath JR, Pedersen BK. Tumor necrosis factor-alpha induces skeletal muscle insulin resistance in healthy human subjects via inhibition of Akt substrate 160 phosphorylation. Diabetes 2005;54:2939-45.

27. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol 2005;98:1154-62.

28. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002;415:339-43.

29. Ostrowski K, Schjerling P, Pedersen BK. Physical activity and plasma interleukin-6 in humans–effect of intensity of exercise. Eur J Appl Physiol 2000;83:512-5.

30. Holmes AG, Watt MJ, Carey AL, Febbraio MA. Ionomycin, but not physiologic doses of epinephrine, stimulates skeletal muscle interleukin-6 mRNA expression and protein release. Metabolism 2004;53:1492-5.

31. Fischer CP, Hiscock NJ, Penkowa M, Basu S, Vessby B, Kallner A, et al. Supplementation with vitamins C and E inhibits the release of interleukin-6 from contracting human skeletal muscle. J Physiol 2004;558:633-45.

32. Henson DA, Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Shannon M, Bolton MR, et al. Influence of carbohydrate on cytokine and phagocytic responses to 2 h of rowing. Med Sci Sports Exerc 2000;32:1384-9.

33. Lancaster GI, Jentjens RL, Moseley L, Jeukendrup AE, Gleeson M. Effect of pre-exercise carbohydrate ingestion on plasma cytokine, stress hormone, and neutrophil degranulation responses to continuous, high-intensity exercise. Int J Sport Nutr Exerc Metab 2003;13:436-53.

34. Li TL, Wu CL, Gleeson M, Williams C. The effects of pre-exercise high carbohydrate meals with different glycemic indices on blood leukocyte redistribution, IL-6, and hormonal responses during a subsequent prolonged exercise. Int J Sport Nutr Exerc Metab 2004;14:647-56.

35. Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Henson DA, Utter A, Davis JM, et al. Influence of mode and carbohydrate on the cytokine response to heavy exertion. Med Sci Sports Exerc 1998;30:671-8.

36. Febbraio MA, Steensberg A, Keller C, Starkie RL, Nielsen HB, Krustrup P, et al. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J Physiol 2003;549:607-12.

37. Starkie RL, Arkinstall MJ, Koukoulas I, Hawley JA, Febbraio MA. Carbohydrate ingestion attenuates the increase in plasma interleukin-6, but not skeletal muscle interleukin-6 mRNA, during exercise in humans. J Physiol 2001;533:585-91.

SHARE THIS POST

Share on facebook
Share on linkedin
Share on twitter
Share on email
EXPLORE OUR ARTICLES
Scroll to Top