How Exercise Can Reduce Your Risk of Coronary Heart Disease

How Exercise Can Reduce Your Risk of Coronary Heart Disease

On my last post about the vilification of fat I indicated I was going to start a series on fat, which I am (and frankly, am looking forward to my next post about saturated fat), but I decided to take a little detour this week.  In one of my classes we have been reading and discussing epidemiological studies on physical activity and mortality rates.  Here is a summary of the last month of class and readings.

According to epidemiological research, physical activity attenuates your risk of all cause mortality, especially cardiovascular disease.

I know what you are thinking…. that is pretty much a “no brainer”.  Well I had the same sentiments and was extremely frustrated with the literature as these studies gave no reasons as to why this is the case. This is one reason I find epidemiological studies frustrating, they often provide more questions than answers, and mainstream media loves to jump on them, often times misconstruing the results.

For the aforementioned class this arose out of, I have to turn in a paper on a topic of our choice.   So, being the compulsive information seeker I am, I decided I wanted to put my thoughts together on HOW exercise reduces your risk of coronary heart disease (CHD).

Last Friday after class I went on what Mat Lalonde calls a “Nerd Safari” (although to be quite honest, I have been using that word for since highschool, but as I am not even in the same realm as the Kraken, I relinquish control of the term to him). I went to the library, parked myself at the computer, tore the search engines apart, printed out tome after tome of reference material and had myself quite a nerdy/wonderful Friday and Saturday marathon of reading, writing, and coffee drinking.  What resulted was about a 20 page paper on potential ways in which physical activity effects the development of CHD. Well it turns out there is a strict 10 page limit for the paper in class…… and as not to waste my efforts I am going to post it for all of you!  So grab a cup of coffee/tea/water/whatever other concoction you brew yourself and dive into the world of the heart and exercise! (Don’t worry, I included some wonderful pictures and diagrams so you can have a breather from text based knowledge every few minutes). Also, don’t worry about all the cytokine names, I give a description of the big players in the post so you can get the gist of what they do.

Exercise Can Help Prevent This!

Cardiovascular disease (CVD) describes myriad diseases that fall under the umbrella of heart disease including diseases of blood vessels, arrhythmias, infections, and congenital defects (Staff, 2011). CVD is the number one cause of death in the world, attributing to roughly 17.3 million deaths in 2008, with an estimated 7.3 million deaths due to coronary heart disease  (CHD)(Cardiovascular diseases (CVDs), 2011). CHD is a disease of narrowing (atherostenosis) and/or hardening (atherosclerosis) of the blood vessels responsible for delivering blood and oxygen to the heart (Chen & Zieve, 2011), in which the narrowing and/or hardening of these vessels are due to a build of plaque inside the coronary arteries. CHD has been outsripping all other causes of death since the turn of the 20th century(Braunwald, 1997)

The development of CHD is not an acute, overnight phenomenon; it progresses over a long period, consequently indicating a chronic condition as the etiology of the disease.  The original theory behind the development of CHD is known as the lipid heart hypothesis; a hypothesis that proposes plasma lipids as the connective factor to the development of CHD. However, half of all myocardial infarctions (MI) occur in patients whom display normal plasma lipid levels(Braunwald, 1997). Although some aspects of the lipid hypothesis hold true, i.e. oxidation of lipoproteins, the lack of high correlation between plasma lipids and CHD or MI indicates the need for a new hypothesis, one that proposes a mechanism to explain CHD independent of plasma lipid levels.  Current research has yielded a new mechanism of CHD with a hypothesis to complement it. The current hypothesis, and the impetus behind this paper, is that inflammation serves as the mechanism behind endothelial damage and CHD independent of plasma lipids. Thus, the focus of this review is on inflammation and CVD, the causes of inflammation, and to propose ways to attenuate systemic inflammation.


The endothelium, an active and dynamic tissue, is a continuous layer of cells separating blood from the vessel wall(Gonzalez & Selwyn, 2003).  Endothelial tissue is involved in maintaining blood circulation and fluidity, regularizes vascular tone, coagulation, and mediates inflammatory responses (Behrendt & Ganz, 2002).  Dysfunction in the endothelial tissue due to the formation of plaque is a characteristic feature of CHD whose cause has been linked with inflammation(Szmitko, Wang, Weisel, de Almeida, Anderson, & Verma, 2003). Endothelial dysfunction is a broad term that implies diminished production or availability of nitric oxide (NO) and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors, such as endothelin-1 (ET-1), angiotensin, and oxidants (Verma & Anderson, 2002). NO, is the driving component in the regulation of vascular tone and vasomotor function, and protects against vascular injury, inflammation, and thrombosis by inhibiting leukocyte adhesion to the endothelium and limiting platelet aggregation(Szmitko, Wang, Weisel, de Almeida, Anderson, & Verma, 2003). Thus, inflammation has vast implications in the development of CHD through a multitude of possible vectors.

Inflammation is a complex reaction to noxious stimuli in which a biological cascade of defense mechanisms occur.  While acute inflammation is necessary to mount a defense against infection or trauma, prolonged inflammation has detrimental health effects and predisposes an individual to CHD(Beavers, Brinkley, & Nicklas, 2010). During an inflammatory immune response, a cascade of inflammatory cytokines is released (nuclear factor kB, interleukin-1, interleukin-6, interleukin-8, TNF-α and fibrinogen), along with the secretion of leukocyte adhesion molecules (VCAM-1), plasminogen activator inhibitor-1 (PAI-1), and chemotactic factors.  The release of interleukin-6 stimulates the release of c-reactive protein (CRP) and serum amyloid A (SAA) from hepatocytes while chemotactic factors encourage the migration of monocytes in the subintimal space(Pearson, et al., 2003).

Gonzalez and Selwyn (2003)

The series of events resulting from this inflammatory process damages the endothelial tissue through the following mechanisms: 1) monocytes and T-lymphocyes bind to the endothelial tissue via the VCAM-1 coupled with the uptake of cholesterol, resulting in atherosclerotic lesions(Libby, 2006), 2) the up regulation of adhesion molecules in endothelial cells due to elevated CRP (Black, Kushner, & Samols, C-reactive Protein, 2004) 3) oxidative stress(Gonzalez & Selwyn, 2003),  4) the inhibition of nitric-oxide synthase (Black, Kushner, & Samols, C-reactive Protein, 2004), 5) increased expression of adhesion molecules by endothelial cells due to elevated CRP (Pasceri, Willerson, & Yeh, 2000), and 6) an increased likelihood of clot development due to increased fibrinogen and PAI-1 (Burstein, 1996).

In the presence of chronic inflammation, atheroma will continue to progress, increasing their vulnerability to disruption and a thrombotic event. Physical disruption of atherosclerotic plaque, typically a fracture of the fibrous cap, results in thrombus formation compromising arterial flow, ultimately in cardiac events. (Libby, 2006)  Inflammation participates in atherosclerosis from its inception and development to its ultimate endpoint, thrombotic complications(Libby, 2006).

Smzitko et al. (2003)

It is clear that inflammation is fundamental in the development of CHD as it results in changes to endothelial tissue, is central in plaque formation, and is responsible for thrombus, MI, and other complications.  The central roles inflammatory cytokines play in the development of CHD indicate their biomarkers as a salient component of risk assessment for CHD in patients.


The term biomarker is defined as a

“Measurable and quantifiable biological parameters (e.g., specific enzyme concentration, specific hormone concentration, specific gene phenotype distribution in a population, presence of biological substances) which serve as indices for health- and physiology-related assessments, such as disease risk, psychiatric disorders, environmental exposure and its effects, disease diagnosis, metabolic processes, substance abuse, pregnancy, cell line development, epidemiologic studies, etc (Biological markers, 1989)”.

The list of biomarkers related to inflammation and CHD is extensive, however, for the purposes of this review we will cover the biomarkers with the greatest correlation to CHD as found in the literature.


Tumor necrosis factor alpha (TNF-α) is a cytokine produced predominantly by adipose tissue and macrophages acts in both an autocrine and paracrine manner (Prins, Niesler, Winterford, Bright, & Siddle, 1997). TNF-α has direct effects on inflammation and the development of CHD and is responsible for creating a downstream cascade of biomarkers and metabolic effects. Direct effects first, TNF-α enhances the expression of adhesion molecules (VCAM-1 and ICAM-1) resulting in the adhesion of monocytes to the surface of endothelial cells, infiltration of the vascular wall, and their transformation in macrophages (Lyon, Law, & Hsueh, 2003).  In its role as a downstream mediator, TNF-α is a key regulator in the production of IL-6 (Oller do Nascimento, Hunter, & Trayhurn, 2004), reduces adiponectin secretion(Ouchi, et al., 2000), and is associated with insulin resistance and type II diabetes (Saghizadeh, Ong, Garvey, Henry, & Kern, 1996).

Although the contribution of TNF-α is complex and circuitous, the state of the evidence suggests that TNF-α is a key proponent in local and systemic inflammation, is highly correlated with CHD, and affects multiple metabolic pathways.  The serum level of TNF-α along with its receptors are independently positively correlated with the presence of CHD, indicating it should be included in the risk assessment of CHD (Porsch-Oezcueruemes, Kunz, Kloer, & Luley, 1999).

C-reactive Protein

C-reactive protein (CRP) is plasma protein that participates in the systemic response to inflammation.  In humans, plasma levels of CRP may rise rapidly and markedly, up to 1000 times the normal limit or more, during acute inflammatory stimulus(Black, Kushner, & Samols, 2004). The production of CRP occurs in the hepatocytes and is primarily regulated by IL-6, this relationship ends up cyclical in nature as increased CRP up-regulates the release of IL-6.

While CRP has anti-inflammatory properties, such as inducing an increase in interleukin-10, an anti-inflammatory cytokine (Szalai, Nataf, Hu, & Barnum, 2002), it has a much more marked effect as a pro-inflammatory agent. It has been shown that CRP up-regulates the expression of adhesion molecules in endothelial cells, inhibits endothelial nitric-oxide synthase (Venugopal, Devaraj, Yuhanna, Shaul, & Jialal, 2002), increases PAI-1, increases IL-1,IL-6, IL-8, and TNF-α (Ballou & Lozanski, 1992).

In specific regard to inflammation and CHD, CRP has been shown to be highly correlated to CHD, with increased CRP levels correlated to increased risk of CHD. Although the mechanism of inflammation as the cause of CHD is sound and the hypothesis has been shown to hold weight, we must keep in mind that currently, the relationship between CRP and CHD is correlational, cause and effect between serum levels of CRP and CHD has not yet been establish.

Interleukin-6 (IL-6)

  IL-6 is a main pro-inflammatory mediator secreted primarily by the cells of the immune system.  IL-6 induces a cascade of pro-inflammatory cytokines and stimulates the production of hepatic acute-phase response proteins including CRP, fibrinogen, and serum-amyloid A (Zocalli, Mallamaci, & Tripepi, 2003).  Elevated levels of circulating interleukin-6 have been seen in severe inflammatory, infectious, and traumatic states and are associated with and increased risk ofCHD (Papanicolau, Wilder, Manolaga, & Chrousos, 1998; 2012).  Aside from inflammation, IL-6 is also positively correlated with obesity, insulin resistance, and glucose intolerance and inhibits secretion of adiponectin (Fernandez-Real & Ricart, 2003).  The mechanism by which IL-6 functions indicates it as a correlative biomarker in a wide range of diseases. This fact, coupled with its role as a mediator of downstream cytokine production indicates it may be a strong predictor of poor health and should be utilized in the assessment of CHD.


Interleukin-8 (IL-8) is a pro-inflammatory chemoattractant cytokine produced by a variety of tissue and blood cells. Unlike other cytokines, such as IL-6, it has specificity for the neutrophil. IL-8 attracts and activates neutrophils in inflammatory regions. In vivo application of IL-8 induces local exudation and a massive, long-lasting accumulation of neutrophils (Bickel, 1993).  IL-8 induces neutrophils to release lysosomal enzymes and to adhere to unstimulated endothelial cells (Detmers, Lo, Olsen, Walz, Baggiolini, & Cohn, 1990). Increased serum levels of IL-8 have been shown to correlate with inflammation, and in some specific cases, IL-8 appears to be the most reliable and predictive surrogate marker to diagnose inflammatory conditions (Penna, et al., 2007).

Vascular Cell Adhesion Molecule 1 (VCAM-1)

VCAM-1 is one of the major endothelial receptors that mediates leukocyte adhesion to the vascular endothelium (Carlos & Harlan, 1994). In an inflammatory state, VCAM-1 is up-regulated, which increases leukocyte recruitment and the development of atherosclerotic plaque.  In studies with knockout mice that were deficient in another type of adhesion molecule (ICAM-1), they found that mice deficient in the adhesion molecule were more protected from atherosclerosis due to inflammation (Nageh, et al., 1997).  The state of the evidence suggests that VCAM-1, as a biomarker, is correlated with a variety of diseases, including CHD and should also be included in risk assessment protocols.

Plasminogen Activator Inhibitor-1 (PAI-1)

Plasminogen activator inhibitor-1 (PAI-1) is produced by the endothelium, adipose tissue, and a select few other tissues.  PAI-1 is the primary inhibitor of both tissue-type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA) and thus inhibits the fibrinolytic process, the physiological degradation of blood clots (Juhan-Vague, Alessi, Mavri, & Morange, 2003). Several prospective research studies have utilized mouse models to test whether elevated PAI-1 due to inflammation promotes thrombosis and atherosclerotic lesion development. The mouse model studies indicate that decreased PAI-1 expression induces a mild hyperfibrinolytic state, and decreases the risk of venous thrombosis without impairing hemostasis (Carmeliet, et al., 1993).  Increased serum PAI-1 levels have also been associated with the development of a first acute myocardial infarction (Thogersen, et al., 1998). This increased PAI-1 level in plasma may participate in increased cardiovascular risk, indicating PAI-1 biomarkers as an additional factor to include in risk assessment for CHD.

Serum Amyloid A (SAA)

Serum amyloid A (SAA) is an acute phase protein that in the blood is bound to high density lipoproteins; SAA is secreted mainly by hepatocytes, and its concentration increases in the blood up to 1000 times during an inflammatory response. It has been suggested that SAA may participate in enhancing the migration of monocytes to inflamed tissues during an acute phase response (Badoloto, et al., 1994). The principal cytokines involved in the induction of A-SAA are IL-1, TNF-α and IL-6 (Uhlar & Whitehead, 1999).  In conditions of chronic inflammation, increased serum levels of SAA can result in a reactive form of amyloidosis, which can bring about loss of organ function (Badoloto, et al., 1994).  Currently, the evidence indicates that SAA is a novel blood biomarker that is more sensitive than CRP alone, and should be included in risk assessment for CHD (Liuzzo, et al., 1994; Bozinovski, et al., 2008).


While in the common lexicon obesity is used synonymously with overweight, the two terms are not the same.  Obesity is defined as excess body fat, while overweight is defined as excess weight (Dugdale & Vorvick, 2012). A person may be overweight from extra lean body mass, bone mineral density, water and is not directly indicative of excess body fat. For the purposes of this article, we will focus on obesity and use the nomenclature of adipose tissue to describe body fat.

Traditionally, adipose tissue has been viewed as a passive reservoir for energy storage (Kershaw & Flier, 2004). Upon discovery of the adipose hormone leptin in 1994, this view was rendered obsolete (Zhang et al., 1994), resulting in the current view of adipose tissue as a complex, highly active endocrine organ which has a direct effect on metabolism.

Adipose tissue as an organ is heterogenous, consisting of: adipocytes, preadipocytes, stromal/vascular cells, and macrophages(Wisse, 2004). In addition to lipid storage, adipose tissue is involved in the release of both pro-inflammatory and anti-inflammtory cytokines(Berg & Scherer, 2005). Thus, adipose tissue contains the metabolic machinery to permit communication with distant organs including the central nervous system (CNS) (Kershaw & Flier, 2004).

Adipose tissue plays a pivotal role in maintaining homeostasis; a properly functioning “adipose tissue organ” is essential to maintaining health, therefore, adverse metabolic consequences are associated with excess adipose tissue. These consequences include: hyperglycemica, dyslipidemia, hypertension, inflammation, and insulin resistance (Kershaw & Flier, 2004). Adipose tissue directly and indirectly effects inflammation both locally, in adipose tissue itself, and systemically.  In the presence of excess adipose tissue, the induction of inflammatory mRNA transcripts in adipose tissue can originate in either adipocytes or their surrounding resident macrophages, and adipocytes and resident macrophages contribute locally to inflammation and synergistically stimulate inflammatory activity of each other(Berg & Scherer, 2005). This effect proves detrimental to health as the onset of inflammation due to excess adipose tissue elicits a self-propagating feedback loop of inflammation in the local adipose tissue, which in turn contributes to increased systemic inflammation.

It has been shown that increased adipose tissue is positively correlated to circulating levels of TNF- α, CRP, IL-6, PAI-1, VCAM-1, SAA, and fibrinogen(Berg & Scherer, 2005). The increase in the markers of inflammation system wide is indicative of secretion of pro-inflammatory cytokines from adipose tissue, but more importantly from other tissues throughout the body.  The marked increase in the acute-phase proteins, CRP and SAA, due to obesity indicates that the release of IL-6 from adipose tissue results in the rise of hepatic derived acute-phase proteins (Ridker, Buring, Hennekens, & Rifai, 2000).

The connection between obesity and inflammation has been strengthened through clinical weight-loss studies in which biomarkers of inflammation were tracked. In these trials weight loss was achieved through myriad modalities, yet all yielded similar results. The studies indicate that reduction in adipose tissue results in decreased circulating levels of TNF-α, IL-6, CRP, PAI-1, ICAM-1, and V-CAM-1 (Nicoletti, et al., 2003; Heilbronn, Noakes, & Clifton, 2001; Giugliano, et al., 2004).

Adipose tissue, specifically adipocytes, secretes hormones and proteins that are only produced by adipocytes and contribute to inflammation and CHD. Two of these hormones, leptin and adiponectin, have only recently been discovered.  While their roles in the human body extend beyond the inflammatory process, for the purposes of this paper we will confine our discussion of them to that process.


            Leptin is a protein hormone produced predominantly adipocytes.  Leptin is involved in a negative feedback loop between adipose tissue and brain(Banks, 2008). It is secreted from fat in proportion to the degree of adiposity, is transported across the blood-brain barrier where it decreases appetite and increase thermogenesis, actions that serve to ultimately decrease adiposity and maintain homeostatic levels of adiposity. However, in the presence of obesity, leptin fails as an adipostat (maintenance of a specific level of body fat) because leptin resistance occurs(Banks, 2008).  Like insulin resistance, when leptin resistance occurs, excess levels of leptin are released and remain in circulation in the blood.

Leptin influences food intake through a direct interaction with the hypothalamus, and while not considered directly inflammatory in nature, leptin serves as a secondary messenger for inflammation and as regulator of immune function(Elmquist, 2001). In a recent study in which the researchers mimicked leptin resistance, they found an increase in the pro-inflammatory cytokine TNF-α along with decrease in the expression of adiponectin, generally considered an anti-inflammatory cytokine(Wang, 2005).  In addition, inflammation as a result of increased levels of serum leptin to arterial endothelial dysfunctions (Bouloumie, Marumo, Lafontan, & Busse, 1999). Aside from the stimulation of inflammatory cytokines, leptin has been shown to   decrease the mRNA expression of PPAR-γ, a regulator for adipocytes and inflammation, in macrophages and macrophage-derived foam cells, and is believed to hasten the development of atherosclerotic lesions (Hwang, et al., 2011). These findings indicate that the increased serum leptin, due to leptin resistance, may correlate to an increased risk of atherosclerosis through multiple mechanisms.



Adiponection is an adipocyte secretory protein that exhibits insulin-sensitizing and anti-inflammatory properties and is believed to be antiatherogenic (Beltowski, 2003). Adiponectin receptors have been found in liver, muscle and endothelial cells, indicating they play a role in systemic inflammation as well as in local adipose tissue (Kadowaki, Yamauchi, Kubota, Hara, Ueki, & Tobe, 2006).

Although adiponectin is secreted by adipose tissue, the level of serum adiponectin has an inverse relationship with the amount of adipose tissue (Arita, et al., 1999). It has been shown that adiponectin acts to decrease expression of adhesion molecules (VCAM-1 and ICAM-1) in endothelial cells in response to inflammatory stimuli(Ouchi, et al., Novel modulator for endothelial adhesion molecules adipocyte-derived plasma protein adiponectin, 1999).  Adiponectin further protects from plaque development as it increases the production of metalloproteinase-1, a tissue inhibitor specific to macrophages (Kumada, et al., 2004).  In addition, adiponectin acts as a antiatherogenic by attenuating suppression of endothelial oxide synthase, the enzyme responsible for generating nitrous oxide, and inhibits cell proliferation due to oxidized low-density lipoproteins through suppression of reactive oxygen species (ROS) (Motoshima, Wu, Mahadev, & Goldstein, 2004).  Ulitmately, adiponectin is an adipocyte-derived hormone that may attenuate the development of CHD; however, in obese individuals serum levels of adiponectin are reduced. Thus, indicating another mechanism in which obesity contributes to inflammation and an increased risk of CHD in obese individuals.  Here is a great diagram by Chudek et al. (2006), that puts the last few paragraphs into a nice, tidy chart.

Currently, state of the evidence implicates an inflammatory state resulting from excess adipose tissue as the mechanism for obesity related CHD.


Insulin resistance is a characteristic feature in most patients with type II diabetes mellitus (DM) and is a defining characteristic in the metabolic syndrome(de Luca & Olefsky, 2008).

Insulin resistance leads to hyperglycemia, which in turn has deleterious effects to the molecules in our blood.  In a state of hyperglycemia, the high levels of glucose in the blood undergo non enzymatic reactions with other molecules in which they are glycated and oxidized. The ultimate result of this process is a product known as advanced glycation end products (AGEs). AGEs have been shown to generate reactive oxygen intermediates. The binding of AGEs to the cell surface by their receptors focuses oxidant stress on cellular targets, ultimately resulting in cellular damage (Schmidt, Hori, Brett, Yan, Wautier, & Stern, 1994).

AGEs accumulate in the vessel wall, exacerbate inflammatory states, and they may perturb cell structure and function.  AGEs have been implicated in both the microvascular and macrovascular complications of diabetes (Goldin, Beckman, Schmidt, & Creager, 2006).The AGE concept proposes that chemical modification and crosslinking of tissue proteins, lipids and DNA affect their structure, function and turnover, contributing to a gradual decline in tissue function and to the pathogenesis of diabetic complications (Rietbrock, 2004). Acute and chronic hyperglycemia is known to enhance advanced glycation(Rietbrock, 2004). AGEs are known to increase oxidative stress, decrease NO synthesis in endothelial tissues, and subsequently increase vascular stiffness.

Insulin resistant states have been associated with increased levels of TNF-α, IL-6, and IL-8 (Hotamisligil, Arner, Caro, Atkinson, & Spiegelman, 1995; Roytblat, et al., 2000; Straczkowski, Dzienis-Strackowska, Stepien, Kowalska, Szelachowska, & Kinalska, 2002). PAI-1 levels have also been shown to increase incrementally as someone transitions from normal to insulin resistant/glucose intolerant to type II DM (Festa, et al., 1999).

Several prospective studies have confirmed that an increase in inflammatory markers at baseline predict type 2 DM and insulin resistance (Pradhan, Manson, Rifai, Buring, & Ridker, 2001; Barzilay, et al., 2001). There is also an established correlation between fasting insulin concentrations and CRP concentrations in plasma (Hak, et al., 1999), thus indicating that insulin resistance and the inflammatory processes are related. It then is problematic in that insulin resistance can arise from a chronic inflammatory state insulin resistance promotes an inflammatory state, one has created a self-propagating cycle of deleterious health states.

Physical Activity Reduces Inflammation

From the earlier discussion, it is obvious that obesity and insulin resistance contribute to, and are resultant of inflammation, and that inflammation is a key component in CHD. Physical activity has been shown to attenuate obesity, insulin resistance, and CHD (need citations).

There are myriad plausible biological mechanisms to explain this relation, and although the exact mechanisms are not well understood, the results of the research substantiate the hypotheses behind many of them. As the focus of the previous section of tihs paper was on inflammation as a mechanism of CHD, and the contributions of obesity and insulin resistance to inflammation, it seems appropriate to address the role physical activity plays in the direct down-regulation of cytokine release, the attenuation of obesity, and improves insulin resistance.

As it is known that physical activity brings about acute inflammatory response, it would appear paradoxical that physical activity would reduce chronic inflammation. It is believed that the etiology of exercise-induced inflammation differs from the inflammation responsible for CHD and other chronic conditions (Ford, 2002).  The research indicates that the acute inflammatory response by exercise brings about training adaptations in human tissue that mitigates chronic inflammation by down-regulating cytokine release from immune cells (Beavers, Brinkley, & Nicklas, 2010).  It is believed this down-regulation is a result of regularly performed muscle contractions that lead to changes cellular communication.

During acute exercise, IL-6 is produced where it serves not only as an inflammatory cytokine but also serves a metabolic role (Keller, Steensberg, Hansen, Fischer, Plomgard, & Pedersen, 2005). Exercise induced IL-6 inhibits the production of TNF-α in the presence of low-grade inflammation, mitigating the direct effect TNF-α has on inflammation along with the cascade of biomarkers that follow it (Starkie, Ostrowski, Jauffred, Febbraio, & Pedersen, 2003).  It has also been shown that exercise training increases basal levels of IL-6R mRNA levels in skeletal muscle (Keller, Steensberg, Hansen, Fischer, Plomgard, & Pedersen, 2005).  This finding suggests that exercise training sensitizes skeletal muscle to IL-6, thus effectively attenuating chronic inflammation by reducing the basal serum levels of IL-6.

The reduction of basal serum IL-6 has implications on the basal levels of other downstream acute-phase proteins such as hepatocyte produce CRP and SAA.  A reduction of acute-phase the proteins CRP and SAA due to physical activity is the pervasive result throughout the literature (Ford, 2002; Kasapis & Thompson, 2005). In addition to the mitigation of TNF-α, CRP, and SAA production, exercise induced IL-6 increases lipolysis and oxidation rates and insulin stimulated glucose uptake into skeletal muscle cells, indicating it may also serve as a mechanism to increase insulin sensitivity (Van Hall, et al., 2003; Carey, et al., 2005).

Obesity directly influences inflammation via an accumulation of excess adipose tissue.  Increased levels of adipose tissue are positively correlated to circulating levels of TNF- α, CRP, IL-6, PAI-1, VCAM-1, SAA, (Berg & Scherer, 2005), while a decrease in adipose tissue due to weight loss is concurrent with a reduction in circulating levels of TNF-α, IL-6, CRP, PAI-1, ICAM-1, and V-CAM-1 (Nicoletti, et al., 2003; Heilbronn, Noakes, & Clifton, 2001; Giugliano, et al., 2004).  Along with a reduction in these inflammatory cytokines, decreased adipose tissue is correlated to decreased leptin levels, increased adiponectin levels and improved insulin sensitivity (Mayer-Davis, et al., 1998).  The literature indicates that, along with the direct mechanisms mentioned above, physical activity may reduce inflammation through a decrease in adipose tissue that generally accompanies weight loss due to exercise.

As previously mentioned, insulin resistance is both a cause and a product of inflammation, and it would appear that reduction in one might lead to a reduction in another.  A wide range of drug trials, genetically modified mouse models, and in vitro cellular manipulations have indeed shown that a reduction of one is correlated to a reduction in the other. A wide range of physiological mechanisms has been proposed to explain how physical activity may improve insulin resistance from up regulation of protein expression of GLUT-4 and insulin receptor substrate-1 (Henriksen, 2002), to exercise dependent lipid metabolism (Kiens, 2006).

Physical activity and exercise have been shown to ameliorate insulin resistance independent of weight loss in some studies, while not in others. In a randomized controlled trial in 2012, a group of researchers found that daily exercise was associated with substantial reductions in insulin resistance when it was accompanied by a reduction in total fat, abdominal fat, and visceral fat (Ross, et al., 2004). In contrast, 12 weeks of aerobic training improved insulin sensitivity in overweight and obese girls without change in body weight, percent body fat (Nassis, et al., 2005).  The contrasting findings of these studies may be explained by the fact that the researchers did not test each participant’s pancreatic function and ability to produce insulin. It may be that the ability to produce insulin was different between the participants of the studies. When one looks at the large body of evidence as a whole, it appears that exercise does indeed ameliorate insulin sensitivity, however the exact mechanisms are not precisely elucidated.

Obesity, insulin resistance, and inflammation appear to be interrelated and circular.  As obesity can lead to insulin resistance and inflammation, insulin resistance can lead to obesity and inflammation, and inflammation can lead to obesity, insulin resistance or both, it is difficult to tell which is the cart and which is the horse. This area is a growing field and the research that lies ahead is exciting and will likely paint a much clearer picture and elucidate some of the confounding factors we see. However, despite their interrelatedness, it is clear that they each can contribute to the development of CHD.

Physical activity reduces inflammation by a multitude of mechanisms, including down-regulation of cytokine release by innate immune cells, decreased inflammatory cytokine release by adipose tissue, reduction in adipose tissue along with a concurrent increase in adiponectin, and increased insulin sensitivity. Although qualitative in nature, I believe it is also important to address the idea that physically active individuals are often more “health conscious” than those who are not. They are more likely to adopt other lifestyle behaviors that reduce their risk of the development CHD, such as healthier food choices, decreased smoking habits, and better stress management.


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