From the Archives: This article originally appeared in the November 2006 issue of the Townsend Letter.

Exercise is a readily accessible, safe, and inexpensive anti-inflammatory medicine. Inflammation is the body's natural means of stimulating healing; but when continuous and chronic, it becomes damaging and detrimental to health. Properly performed, exercise releases signaling molecules that stimulate a unique healing response which couples both inflammatory and anti-inflammatory mechanisms to repair, regenerate, and grow stronger tissue. Understanding the history and mechanism behind these effects creates new prescriptive opportunities for exercise. Unlike drugs, which have single targets and ignore the weblike interactions in the body, exercise works with the body's innate intelligence to produce broadly beneficial effects that improve whole-body function. High-intensity, short-duration movement that is tailored to the individual, uses short rest periods, and engages the whole body may be the chief means of attaining anti-inflammatory effects from exercise.

The human body was designed for activity and evolved with movement. The vast majority of human existence was steeped in the harsh realities of the natural world. Our ancestors did low-intensity activity all day, every day, and were forced to engage in vigorous movement to avoid danger and procure food. This extreme physical reality made injury and infection commonplace. Inflammation produced in response to physical insults was the body's natural protective mechanism for healing.

While inflammation is often thought of as destructive, it is actually a closely orchestrated event that first produces pain, redness, swelling, heat, and tissue destruction, but then is followed by repair. Over the millennia, the human body evolved and used acute inflammation to heal, repair, and regenerate itself. Movement was an essential part of this healing and regenerative process. The unique anti-inflammatory effects of movement have been circumvented in the modern era. With the arrival of the industrial and technological revolutions, human movement came to a crawl. This left inflammation unchecked by the anti-inflammatory and growth-stimulating effects of exercise.

In modern day, the human body is confronted with persistent stress. Along with this stressful lifestyle, humans no longer depend on movement and its growth-stimulating and healing effects. As a result, acute and controlled inflammation has given way to chronic, low-level inflammation. This type of inflammation is less detectable by objective or subjective measures, making it more insidious in nature. The lifestyle of prehistoric humans had substantial risks, yet their movement patterns kept chronic inflammation at bay. Without the balancing effects of exercise, inflammation is allowed to smolder at a low level, damaging tissue and destroying the quality and quantity of life.

Myokines: Muscle-Body Messengers
Every time the body moves, muscles release signaling molecules that communicate to the rest of the body. The endocrine properties of muscle, like fat, have been confirmed.^3,4,6 In the case of muscle, compounds called myokines are released in response to voluntary contraction. Myokines are cytokines, yet are derived specifically from muscle. These myokines give instructions to the body about how to function, and they hold the key to controlling chronic inflammation. The most important myokine related to muscle and inflammation is IL-6. When muscle contracts, IL-6 is released.

IL-6 is a well-known cytokine and has long been thought to be inflammatory in nature as part of what is known as the inflammatory triad: TNF-alpha, IL-1, and IL-6. However, IL-6 seems to behave differently depending on its origin, amount, and other cytokines around it. When released from muscle, and in high concentrations without TNF-alpha and IL-1, IL-6 is anti-inflammatory.^10,12 In fact, IL-6 acts to reduce the amount of TNF-alpha and IL-1 in circulation by increasing the cytokine inhibitors IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR).^5,7,8 IL-1ra antagonizes the IL-1 receptor, decreasing IL-1 effects, while sTNFR binds up TNF-alpha before it can react at its target cells. At the same time, IL-6 triggers the release of the major anti-inflammatory cytokine IL-10.^7,8

It appears that exercise-induced IL-6 has unique action as opposed to TNF-alpha-mediated release of IL-6.¹⁰ Exercise causes a huge rise in IL-6, far and above TNF-alpha levels. This is in sharp contrast to infection or sepsis, which shows an exponential rise in both. The ratio of IL-6 to TNF-alpha may be the real concern in regard to chronic inflammation. Epidemiological studies on TNF alpha and IL-6 genetic polymorphisms support this, showing that those with the highest TNF alpha and lowest IL-6 levels have the greatest risk of diabetes.³⁷ Other researchers support TNF alpha as the real inflammatory culprit.¹⁰ They speculate IL-6 levels may be a marker of whole-body TNF-alpha levels and could be acting in direct opposition to the more inflammatory cytokines. The IL-6 effect implicates exercise as a first-line defense against inflammation and may explain the "counterintuitive" findings on the benefit of resistance training in highly inflammatory diseases like rheumatoid arthritis.²⁶

IL-6: The Exercise Factor
For some time, science has been searching for a molecule that could account for the acute metabolic effects of exercise. Exercise reduces "all cause mortality," due to its effects on the leading killers: heart disease, diabetes, and cancer.^35,36 IL-6 is also beginning to be shown to be protective against diseases like diabetes.^12,14,16 These same diseases have strong links to inflammation, which is now suspected as a major underlying cause. It has long been thought that exercise's impact on weight loss was the reason behind this. However, IL-6 also plays a role as a mediating factor in exercise's effects on fuel metabolism.^1,3,4,6,15 The broad effects IL-6 has on inflammatory cytokines and fuel metabolism, plus its ability to "talk" to the brain, liver, and adipose tissue, have some researchers thinking it is the best candidate for the elusive exercise factor.⁶

As muscle contracts, the genes controlling IL-6 production are turned on. The degree of IL-6 released from muscle is directly proportional to the amount of muscle being contracted; the more muscle used, the greater the response.^5,7,38,40 IL-6 also shows a tight relationship to muscle glycogen and exercise intensity. When muscle sugar stores begin to decrease, an intensity threshold is breached, and much larger amounts are released.⁴⁰ Rising exercise intensity, full-body muscle contraction, and muscle glycogen depletion are the major exercise elements enhancing IL-6 release from muscle.^11,12,38 These factors together can induce an increase of plasma IL-6 that is 20- to 100-fold over resting levels.^5,41 When at these levels, IL-6 begins to exert influence over the body, relaying messages about the metabolic needs of the muscle. In this way, IL-6 acts more like a hormone than a cytokine, sending communications from muscle to adipose tissue, immune cells, and the liver. These messages instruct the body to burn fat, control glucose regulation, inhibit the production of the pro-inflammatory cytokines, and ultimately generate a fully anti-inflammatory effect through the release of IL-10.⁸ IL-10 is a potent reducer of TNF-alpha and IL-1 in its own right.¹⁰

From the above scenario, it should be apparent that the ability to harness IL-6 through exercise can have a significant effect, not only on inflammation, but on whole-body fuel usage and tissue repair. This process is far different than the usual chronic inflammatory scenario. A situation of chronic inflammation is one where TNF alpha is elevated along with IL-6 and IL-1. Exercise-induced, muscle-derived IL-6 shifts the balance, causing a reduction in TNF-alpha and IL-1 with a simultaneous rise in IL-10.

Other Effects of Exercise-Induced IL-6
In addition to its more direct effect, exercise-induced IL-6 has other secondary effects that account for increased benefits. 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD1) is an enzyme that should be on the radar of physicians. It is responsible for the conversion of cortisone into active cortisol. This cortisol/cortisone ratio is important in keeping the detrimental effects of cortisol at bay by deactivating it to cortisone. This enzyme is present in visceral adipose and is overly active in the overweight and obese.¹³ This is an important revelation as it points to visceral adipose tissue as a new site of cortisol production. TNF-alpha and IL-1 beta are both shown to upregulate 11beta HSD1 and contribute to total glucocorticoid production.¹³ IL-6 is a potent inhibitor of both TNF-alpha and IL-1 beta, and the largest amounts are released through exercise. Intense exercise potentiates these effects by increasing sympathetic stimulation of alpha 2 receptors as well as ACTH (adrenocorticotropic hormone), all of which have independent effects in suppressing HSD1 activity. The ability to blunt the HSD1 enzyme is beneficial in controlling obesity and diabetes, and intense exercise may be the best way to effect these changes.

In addition to the cytokine effects, IL-6 crosses over into hormonal action and allows the muscle to "talk" to the adipose tissue.⁴ In response to exercise, IL-6 from muscle acts at distant sites, including the liver and adipose tissue. Its major action at these sites is to release energy substrate to fuel continued movement. IL-6 is a potent stimulator of adipose tissue fatty acid oxidation and is a major factor in liver glycogenolysis.^1,4 While the mechanism for this action has not yet been fully elucidated, studies have confirmed that IL-6 has direct effects on the expression of AMP-kinase and hormone sensitive lipase, two chief fuel-regulating enzymes in human tissue.^15,47-48

Finally, IL-6 has the ability to cross the blood-brain barrier, having direct effects on the brain. In fact, the brain itself produces IL-6 in response to exercise as well. This sparks curiosity as to what IL-6 is doing to the brain. Animal studies show that IL-6 is having a direct and important effect on the brain. These studies show IL-6 playing a role in appetite regulation, fuel regulation, and body composition.¹⁶

IL-15, The Arnold Cytokine
Along with IL-6, IL-15 is another myokine that is working to reduce inflammation in less direct ways. This cytokine works by interacting with transcriptions factors, such as PPAR delta, decreasing adipose tissue size while at the same time increasing muscle contractile elements and size.^51-55 The end result will be less adipocytokine release (inflammation) due to a decreased fat mass, and a higher potential secretion of myokines (anti-inflammation) due to a greater contractile potential.

It appears that IL-15 is emerging as a potent antiobesity weapon and may explain why resistance exercise, which does not typically burn as many calories as aerobic exercise, dramatically affects body composition. We like to refer to this myokine as the Arnold Cytokine after Arnold Schwarzenegger, famous bodybuilder/actor, now governor of California. Bodybuilders are able to develop extremely lean and muscular physiques while focusing almost all their attention on high intensity resistance exercise as opposed to aerobic exercise.

Research shows that IL-15 release is twofold higher in type-2 dominated muscle tissue and that resistance exercise doubles IL-15 concentrations 24 hours after exercise.^51,52 This shows a novel mechanism by which resistance exercise is a potent stimulator of fat burning. The effects of IL-15 are not the same in type-1 muscle fibers, which dominate in aerobic activities. IL-15 has profound effects on reducing adipose tissue size while at the same time acting to increase muscle tissue. These effects are desirable, since muscle mass is frequently lost along with fat in aerobic-centered exercise programs.

IL-8 Angiogenesis
IL-8 is another myokine that may help the body heal through ability to build greater blood supply. It is produced whenever the muscle encounters low oxygen supply, such as when it is undergoing intense anaerobic exercise. It appears that IL-8 is a potent angiogenic factor that signals the body to begin to build new blood vessels to increase blood supply. The muscle release of IL-8 is intuitive and self-serving for the muscle, allowing the tissue to meet the demands of activity the next time around. It appears that IL-8, like IL-6, is associated with intensity of exercise. It is released in highest concentration as a response to exhaustive aerobic exercise and during eccentric contraction. The myokine appears to act locally, inducing the angiogenic effects in the muscle tissue only. This is in contrast to IL-6 and IL-15, which, despite being cytokines, cross over into hormonelike action when induced through exercise.⁵⁶

Exercise Approaches to Inflammation
IL-6's release from muscles cells is not a nervous-system phenomenon and is not based on muscle injury. It seems the impetus for IL-6 release is mechanical.^6,40 In other words, just the act of movement is all that is required. However, there are ways to amplify IL-6 production during exercise. The science of exercise metabolism now goes far beyond simple calories. The ability to harness the far-ranging hormonal and cytokine effects of exercise can be accomplished through the use of short-duration, high-intensity exercise techniques used in athletic populations for decades. Although the term "high-intensity" may give pause, these tools and techniques can be adapted to use in even the least fit and most inflamed populations.^17-26

Before discussing the techniques in this approach to exercise, it is important to define why short, intense exercise is best. The damage associated with chronic inflammation is compounded by a lack of offsetting growth factors. The body produces these growth factors in response to intense exercise. Testosterone and especially growth hormone are known to be factors linked closely with intensity. The word intense, as we use it here, means exercise that is glycogen-depleting; that is, exercise that significantly reduces the body's muscle and liver sugar stores. Only two types of exercise are able to produce these effects: long-duration exercise lasting hours, or short, intense, sprint-type exercise. There are obvious constraints to prescribing hour-long exercise sessions, since time shortage is the number one reason cited for lack of exercise participation. Consequently, short, intense exercise is not only more beneficial, but more realistic. In addition, the overall hormonal response to long-duration exercise is counterproductive, as it raises cortisol levels above the body's ability to compensate with growth promoters.^27-34

High-intensity exercise using short bursts of all-out effort significantly alters glycogen stores and can be easily managed through the use of intervals – periods of all-out effort interspersed with rest. This type of activity is manageable by those considered most frail in terms of exercise prescription, including chronic obstructive pulmonary disease (COPD),^19-20 postbypass,²² congestive heart failure,²³ and even heart transplant patients.¹⁸ This type of anaerobic stimulus more realistically mimics real-world challenges and allows for self-paced exercise that is safe, tolerable, and more beneficial for many heart and lung patients.^17-25 Cardiac patients also have less risk with this type of activity, as it has more favorable effects on Stress Test (ST) segment changes and heart rate variability.^21,24-25

This type of exercise also makes sense because it creates a hormonal environment that produces sustained fat-burning as well as muscle growth.^42-44 The amount of glycogen reduction is directly correlated to IL-6 release, and high-intensity exercise is shown to increase IL-6 and catecholamines together.^5-6,11,49 Catecholamines have their own independent effect in lowering TNF alpha and IL-1, synergistically enhancing IL-6. Combining these known effects with techniques that can deliver the same benefit in less time presents the opportunity to supply these anti-inflammatory effects in short time periods.^45,46

The Anti-Inflammatory Workout.
The most efficient way to generate an ample IL-6 response to exercise is to combine resistance training and aerobic exercise in one workout. This allows the body to quickly dip into anaerobic metabolism where glycogen stores are rapidly depleted to sustain energy. Relying strictly on aerobic metabolism makes significant glycogen reduction unlikely in the time periods most people are willing to exercise. Combination workouts also allow the body to efficiently switch from aerobic to anaerobic metabolism and back again. This is a useful metabolic skill, considering that cardiovascular events can be induced by unexpected anaerobic challenges that the body is not prepared to handle. Examples would be shoveling the first winter snow or running to catch an airplane. It is prudent to train this energy system, and it accomplishes significant risk reduction.^17-25

The exercises used also should move away from more conventional types. Those that involve large muscles and combine multiple joints stimulate a large amount of muscle contraction and supply a better stimulus for IL-6 release.⁶ Hybrid exercises that combine two or more traditional types of exercise in one movement are able to stimulate large amounts of muscle and cut down on time in the gym. An example would be combining a squat exercise with a shoulder press. Rather than performing the exercises separately, they are merged so that the completion of the squat is immediately followed by the press in one single movement. This same principle can be used to create a whole range of exercises that are more functional, less monotonous, and more efficient than traditional training methods.

Other useful tools to incorporate into the workout include short rest periods as well as metabolic and mechanical failure. While the failure component is not necessary to induce IL-6 release, it will ensure a large IL-6 surge. The ability to maintain exercise and the onset of a muscle "burn" is a good indication the muscle sugar supply is being taxed. The rest periods should be taken when needed, with exercise being resumed as quickly as possible. The ability to speak is a good indication of exertion and usually corresponds to 85% of one's V02 max.⁵⁰ A person should push until he has to rest and then rest until he can push again. Using heart rate measures coupled with exertion scores based on the ability to speak, exercise participants can create a safe workout that delivers a large dose of anti-inflammatory mediators.

The easiest way to incorporate the short rest periods and failure concept is to use supersets and hybrid movements. A superset consists of two exercises done back to back without rest. A short cycle can be set up so that three to four exercises are done back to back in succession and repeated until the participant must stop or reaches her limit. Once that occurs, the participant rests until she can continue again, using the ability to talk as a guide. The use of a stopwatch allows the exerciser to time himself for ten, 20, or 30 minutes. This creates an efficient workout that induces a large IL-6 response and also excels at increased fat-burning and optimal hormone metabolism.

Final Comments
Inflammation is one of the body's natural protective mechanisms, but when it becomes chronic, it can turn destructive. Movement has historically kept inflammation in check through its anti-inflammatory mechanisms. As human movement has decreased, chronic inflammation has become rampant and contributes to all the major killers. The power of intense exercise to combat inflammation has been illustrated. A fast-moving workout using full body movements, minimizing rest, and focusing on glycogen depletion can insure adequate anti-inflammatory effects. This same style of workout can be tailored to the fitness level of the participants through the use of a self-controlled interval format. Heart-rate monitoring and perceived exertion measures based on the ability to speak allow for a safe and effective workout in even the frailest. Exercise is an underutilized healing modality despite its known benefits. With an understanding of its anti-inflammatory effects, exercise can now be seen as a useful adjunct or first-line therapy in all diseases of chronic inflammation

This article originally appeared in the November 2006 issue of the Townsend Letter.

Notes
1. Peterson 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. Available at: http://ajpendo.physiology.org/cgi/content/full/288/1/E155.
2. Neels et al. Inflamed fat: what starts the fire? J Clin Invest. 2006;116(1):33-35. Available at: http://www.jci.org/cgi/content/full/116/1/33.
3. Tomas et al. Metabolic and hormonal interactions between muscle and adipose tissue. Proceedings of the Nutrition Society. 2004;63:381-385. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=
Abstract&list_uids=15294059&query_hl=6&itool=pubmed_docsum. (one link, two lines)
4. Pederson et al. Muscle-derived IL-6 – a possible link between skeletal muscle, adipose tissue, liver and brain. Brain Behav Immun. 2005;19:371-376. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
5. Ostrowski et al. Physical activity and plasma IL-6 – effect of intensity of exercise. Eur J Appl Physiol. 2000;83:512-515.
6. Pederson et al. Searching for the exercise factor: Is IL-6 a candidate? J Muscle Res Cell Motil. 2003;24:113-119.
7. Pederson et al. The cytokine response to strenuous exercise. Can J Physiol Pharmacol. 1998;76:505-511.
8. Steensberg et al. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol Endocrinol Metab. 2003;285:E433-E437.
9. Trujillo et al. TNF alpha and glucocorticoids synergistically increase leptin production in human adipose- role for p38 MAPK. J Clin Endocrinol Metab. 2006;91(4):1484-90.
10. Petersen et al. The anti-inflammatory effect of exercise. J Appl Physiol. 2005;98:1154-1162. Available at: http://jap.physiology.org/cgi/content/full/98/4/1154
11. Peake et al. Plasma cytokine changes in relation to exercise intensity and muscle damage. Eur J Appl Physiol. 2005;95(5-6):514-521.
12. Bruunsgaard et al. Physical activity and modulation of systemic low-level inflammation. J of Leukoc Biol. 2005;78(4):819-835.
13. Friedberg et al. Modulation of 11beta-hydroxysteroid dehydrogenase type 1 in mature human adipocytes by hypothalamic messengers. J Clin Endocrinol Metab. 2003;88(1):385-393.
14. Carey et al. IL-6 and TNF-alpha are not increased in patients with type 2 diabetes: evidence that plasma IL-6 is related to fat mass and not insulin responsiveness. Diabetologia. 2004;47:1029-1037.
15. Watt et al. Hormone-sensitive lipase is reduced in the adipose tissue of patients with type 2 diabetes mellitus: influence of IL-6 infusion. Diabetologia. 2005;48:105-112.
16. Wellenius et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med. 2002;Jan;8(1):75-79
17. Tanasescu et al. Exercise type and intensity in relationship to coronary heart disease in men. JAMA. 2002;Oct;288(16):1994-2000.
18. Pokan et al. Effect of high-volume and high-intensity endurance training in heart transplant recipients. Med Sci Sports Exerc. 2004;36(12):2011-2016.
19. Kaelin et al. Physical fitness and quality of life outcomes in a pulmonary rehabilitation program utilizing symptom limited interval training and resistance training. J Exerc Physiol. 2001;Aug;4(3):30-37.
20. Butcher et al. The impact of exercise training intensity on change in physiological function in patients with chronic obstructive pulmonary disease. Sports Med. 2006;36(4):307-325.
21. Pichot et al. Interval training in elderly men increases both heart rate variability and baroreflex activity. Clin Auton Res. 2005;15(2):107-115.
22. Meyer et al. Interval versus continuous exercise training after coronary bypass surgery: a comparison of training-induced acute reactions with respect to the effectiveness of the exercise methods. Clin Cardiol. 1990;Dec;13(12):851-861.
23. Meyer et al. Interval training in patients with severe chronic heart failure: analysis and recommendations for exercise procedures. Med Sci Sports Exerc.1997;Mar; 29(3):306-12.
24. Ehsani et al. Improvement of left ventricular contractile function by exercise training in patients with coronary artery disease, Circulation. 1986;74:350–358.
25. Warburton et al. Effectiveness of high-intensity interval training for the rehabilitation of patients with coronary artery disease. Am J Cardiol. 2005;95(9):1080-1084.
26. Hakkinen et al. Effects of prolonged combined strength and endurance training on physical fitness, body composition and serum hormones in women with rheumatoid arthritis and in healthy controls. Clin Exp Rheumatol. 2005;23(4):505-512.
27. Ottosson et al. Effect of cortisol and growth hormone on lipolysis in human adipose tissue. J Clin Endocrinol Metab. 2000;85(2):799-803.
28. Crawford et al. Randomized placebo-controlled trial of androgen effects in muscle & bone in men requiring long-term glucocorticoid treatment. J Clin Endocrinol Metab. 2003;88(7):3167-3176.
29. Bjorntorp et al. Hormonal control of regional fat distribution. Hum Reprod. 1997;Suppl 1:21-25.
30. McCarty et al. Modulation of adipocyte lipoprotein lipase expression as a strategy for preventing or treating visceral adiposity. Med Hypotheses. 2001;57(2):192-200.
31. Ottosson et al. (1995). Growth hormone inhibits lipoprotein lipase activity in human adipose tissue. J Clin Endocrinol Metab. 180, 936-941.
32. Samra et al. Effects of physiological hypercortisolemia on the regulation of lipolysis in subcutaneous adipose tissue. J Clin Endocrinol Metab. 1998;83, 626-631
33. Djurhuus et al. Additive effects of cortisol and growth hormone on regional and systemic lipolysis in humans. Am J Physiol. 2004;E286, 488-494.
34. Djurhuus et al. Effects of cortisol on lipolysis and regional interstitial glycerol levels in humans. Am J Physiol. 2002;E283, 172-177.
35. Abramson et al. Relationship between physical activity and inflammation among apparently healthy middle-aged and older US adults. Arch Intl Med. 2002;162:1286-1292.
36. Blair et al. Is physical activity or physical fitness more important in defining health benefits? Med and Science in Sports and Exercise. 2001;33:S379-S399.
37. Kubaszek et al. Promoter polymorphisms of the TNF alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: The Finnish diabetes prevention study. Diabetes. 2003;52:1872-1876.
38. King et al. Inflammatory markers and exercise: Differences related to exercise type. Med Sci Sports Exerc. 2003;35:575-581.
39. Steensberg et al. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol. 2001;537(Pt 2):633-639.
40. Steensberg et al. IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab. 2002;Dec;283(6):E1272-278.
41. Ostrowski et al. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol. 1999;Feb;515(1):287-291.
42. Kraemer et al. Endogenous anabolic hormonal and growth factor responses to heavy resistance exercise in males and females. Int J Sports Med. 1991;12:228-235.
43. Osterberg et al. Effect of acute resistance exercise on post-exercise oxygen consumption and resting metabolic rate in young women. Int J Sport Nutr Exerc Metab. 2000;10:71-81.
44. King et al. A comparison of high intensity vs. low intensity exercise on body composition in overweight women. Med Sci Sports Exerc. 2001;33:A2421
45. Osterberg et al. Effect of acute resistance exercise on postexercise oxygen consumption and resting metabolic rate in young women. Int J Sport Nutr Exerc Metab. 2000;10(1):71-81.
46. Schuenke et al. Effect of an acute period of resistance exercise on excess post-exercise oxygen consumption: Implications for body mass management. Eur J Appl Physiol. 2002;86:411-417.
47. Kelly et al. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem Biophys Res Commun. 2004;320(2):449-454.
48. MacDonald et al. Interleukin-6 release from human skeletal muscle during exercise: relation to AMPK activity. J Appl Physiol. 2003;95(6):2273-2277.
49. McMurray et al. Interactions of metabolic hormones, adipose tissue and exercise. Sports Med. 2005;35(5):393-412.
50. Meckel et al. The effects of speech production on physiological responses during submaximal exercise. Med Sci Sports Exerc. 2002;34(8):1337-1343.
51. Nielson et al. Expression of interleukin-15 in human skeletal muscle—effect of exercise and muscle ?bre type composition. J Physiol. 2007;584(1):305–312.
52. Riechman et al. Association of interleukin-15 protein and interleukin-15 receptor genetic variation with resistance exercise training responses. J Appl Physiol. 2004;97:2214–2219.
53. Argilés et al. Therapeutic potential of interleukin-15: a myokine involved in muscle wasting and adiposity. Drug Discov Today. Epub 2008 December 16.
54. Quinn et al. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am J Physiol Endocrinol Metab. 2009;296(1):E191-202.
55. Nielson et al. Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J Clin Endocrinol Metab. 2008 November; 93(11):4486-4493.
56. Pederson et al. Role of myokines in exercise and metabolism. J Appl Physiol. 2007;103:1093-1098.

Jade Teta, ND, CSCS
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