Diabetes, Obesity and Metabolism 15 (Suppl. 3): 5160, 2013.

2013 John Wiley & Sons Ltd

The effect of physical activity on mediators of inammation

M. A. Nimmo, M. Leggate , J. L. Viana & J. A. King
School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, Leicestershire, UK

Being physically active and undertaking exercise on a regular basis are critical lifestyle behaviours which protect against the development of
numerous chronic metabolic conditions. One of the key mechanisms by which physical activity exerts favourable health effects appears to be
due to its capacity to reduce chronic low-grade inammation. Single bouts of exercise have a potent anti-inammatory inuence with recent
advances describing important effects of acute exercise on inammatory mediators produced within skeletal muscle (myokines), adipose
tissue (adipokines) and leucocytes. The accumulated effects of physical activity or exercise training on systemic inammation have been
studied widely within epidemiological research; however, information from intervention trials is still emerging. Current data suggest that the
most marked improvements in the inammatory prole are conferred with exercise performed at higher intensities, with combined aerobic
and resistance exercise training potentially providing the greatest benet. The purpose of this review is to describe recent advances in our
understanding surrounding the acute and chronic effects of physical activity on key mediators of inammation. Within this, particular attention
is given to the interleukin-6 system owing to its apparent centrality in mediating the anti-inammatory effects of exercise.
Keywords: anti-inammatory, exercise, IL-6, inammation, physical activity
Date submitted 21 March 2013; date of final acceptance 27 April 2013

Introduction
The health benefits of regular exercise are well documented,
with an abundance of evidence pointing to a decreased risk of
developing several chronic diseases, including cardiovascular
disease (CVD), metabolic syndrome, type 2 diabetes (T2D)
and several cancers [1]. These long-term conditions, amongst
others, have been consistently reported to be associated with
an underpinning chronic low-grade inflammation [2].
An inactive lifestyle leads to the accumulation of adipose
tissue on the simple premise that energy expenditure is
likely to be lower than energy intake. Excess adipose tissue
is accompanied by infiltration of immune cells, increased
release of adipokines and the development of systemic lowgrade inflammation. Exercise can impede the accumulation of
adipose tissue directly through increasing energy expenditure,
and can promote cardiovascular health by improving the blood
lipid profile, which is presumed to limit the production of
atherosclerosis. However, the protective effect of a physically
active lifestyle against chronic diseases can be additionally
ascribed to the anti-inflammatory effects of exercise [3].
Chronic low-grade inflammation is characterized by a twoto fourfold elevation of circulating pro- and anti-inflammatory
molecules above those seen in healthy individuals [4]. The
impact of physical activity on inflammation has received
Correspondence to: Prof. Myra A. Nimmo, School of Sport, Exercise and Health Sciences,
Loughborough University, Loughborough, Leicestershire LE11 3TU, UK.
E-mail: m.a.nimmo@lboro.ac.uk

Present address: School of Life, Sport & Social Sciences, Edinburgh Napier University,
Sighthill Court, Edinburgh EH11 4BN, UK

significant attention in recent years, and the identification

of skeletal muscle as an endocrine organ, producing a diverse
array of metabolic factors, has provided a mechanistic link
between muscle contraction and its beneficial influence on
systemic inflammation and health [5].
The spectrum of physical activity is incredibly broad,
ranging from the relatively new paradigm of physical
inactivity/sedentary behaviour physiology to adaptations
associated with intermittent high-intensity exercise training
(HIIT) (figure 1). This article reviews the current evidence
supporting how physical activity can manipulate the release
of inflammatory proteins from skeletal muscle (myokines),
leucocytes and adipose tissue (adipokines), and the effect
that they confer on health. This article also reviews evidence
describing the impact of various forms of exercise training on
chronic low-grade inflammation.

Acute Exercise and the Release of

Anti-inammatory Mediators
Skeletal Muscle
Within recent years it has been recognized that skeletal muscle
is a highly metabolically active organ, producing and secreting
an array of molecules in response to contraction [5]. The
products of this tissue have been termed myokines and have
been shown to exert many diverse effects, some of which occur
locally within the skeletal muscle itself whilst others act distally
within other organs and tissues including the liver, pancreas,
adipose tissue and cardiovascular system [6]. Although at
present our understanding of skeletal muscle as an endocrine
organ is far from complete, available evidence suggests that

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Figure 1. The physical activity spectrum. METs, metabolic equivalents (multiples of resting metabolism); HIIT, high-intensity intermittent training;
*, sprint cycling is the commonest form of HIIT.

contraction-induced myokine production may mediate many

beneficial physiological effects of regular exercise which
favourably impact upon metabolic health [7]. Currently, several myokines have been characterized; however, undoubtedly
the most well studied is the cytokine interleukin-6 (IL-6). This
interest stems from the fact that IL-6 displays the most marked
response to acute exercise stimuli while also being thought to
orchestrate the anti-inflammatory effect of acute exercise [8].
Resting concentrations of IL-6 in young, healthy individuals
are typically very low with two- to threefold higher levels
being apparent in older adults or those with metabolic disease
such as T2D and CVD. At rest, the secretion of IL-6 from
skeletal muscle is minimal, with the majority being produced
from leucocytes and adipose tissue [9]. During acute exercise,
muscle contraction stimulates the release of IL-6 from the
skeletal muscle, with circulating levels increasing over 100-fold
with intense and prolonged exercise, for example, marathon
and ultra-endurance events [10]. Typically, however, more
moderate responses are observed which are proportional to
the exercise intensity and duration, individual fitness level
(inversely) and muscle mass utilized by the specific exercise
modality [9]. Thus, when exercise duration and external
workload are matched, HIIT induces a greater IL-6 response
than moderate-intensity continuous exercise (figure 2, upper
panel) [11].
For many years it had been postulated that a so-called
exercise factor was responsible for mediating several metabolic
responses that occur during exercise. However, until recently
the candidate remained elusive. Skeletal muscle-derived IL-6
has now been identified as a key metabolic intermediary and
research has defined IL-6 as an energy sensor, functioning
to preserve fuel availability during exertion [12]. Specifically,
during exercise IL-6 serves to augment hepatic glucose and
adipose tissue fatty acid release to provide sufficient fuel
to meet the extra metabolic demand. Accordingly, exercise
performed with depleted muscle glycogen or with exogenous
glucose ingestion has been shown to augment and suppress the
exercise-induced IL-6 response, respectively [12]. These effects
of IL-6 on the liver and adipose tissue are mediated through
the activation of AMP-activated protein kinase (AMPK).
During exercise the release of IL-6 can be stimulated
by increased intracellular calcium content, a result of
muscle contraction, with subsequent downstream activation of

52 Nimmo et al.

Figure 2. Interleukin-6 (upper panel) and sIL6R (lower panel) responses

to continuous, moderate intensity exercise (grey bars) and intermittent
high-intensity exercise (black bars) matched for protocol duration and
external workload done (n = 11). *, Significant trial effect (p = 0.018);
, significant time effect (p < 0.05). Adapted with permission from Ref.
[11].

transcription factors that induce an increase in IL-6 production

[6]. This makes human skeletal muscle unique in being able to
produce IL-6 independent of the pro-inflammatory cytokine
tumour necrosis factor- (TNF-) [13]. Furthermore, in
contrast to adipose-derived IL-6, which is commonly thought
of as pro-inflammatory, episodic elevations in skeletal musclederived IL-6 trigger an anti-inflammatory cascade by inhibiting
the release of pro-inflammatory cytokines (TNF- and IL-1])
via the stimulation of their antagonistic receptors [8]. The
capacity of IL-6 to blunt TNF- activity has been demonstrated

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in several murine models and in humans following exogenous

IL-6 administration, showing a key regulatory role of IL-6 over
TNF- [14]. In addition to suppressing pro-inflammatory
factors, exercise-related IL-6 also triggers the release of IL-10
[8], a potent anti-inflammatory molecule, which itself directly
inhibits the synthesis of several pro-inflammatory mediators,
particularly of the monocytic lineage such as IL-1, IL-1,
TNF-, the chemokines IL-8 and macrophage inflammatory
protein-1 (MIP-1). These inflammatory mediators play a
key role in propagating inflammatory responses and recruiting
immune cells to the site of inflammation. Prolonged exercise
can also lead to the release of C-reactive protein (CRP)
on the following day [8]. This may confer an additional
anti-inflammatory effect by promoting the induction of antiinflammatory cytokines from circulating monocytes and by
suppressing the synthesis of pro-inflammatory cytokines in
tissue macrophages. Additionally, exercise may also induce an
acute anti-inflammatory effect by stimulating the production
of cortisol and adrenaline, two hormones which exert potent
anti-inflammatory effects. Muscle-derived IL-6 may partly be
responsible for the cortisol response to exercise [9].
An early indication of the fact that IL-6 alone could not
be the sole mediator of these anti-inflammatory effects was
identified by Febbraio et al. who showed that recombinant
IL-6 infusion only elevated circulating glucose when skeletal
muscle was active. This evidence suggested that the exercising
muscle provided a co-factor for IL-6 to function fully [15].
Specifically, research has shown that both IL-6 and the IL-6
receptor (IL-6R) are required to be present in order to initiate
glucose uptake at physiological levels [16]. At rest, expression
of this membrane-bound receptor in skeletal muscle is limited,
with significantly greater expression found in hepatocytes and
leucocytes [17]. IL-6 can, however, bind with the circulating
soluble receptor (sIL-6R) which increases after endurance
exercise and remains elevated for prolonged periods after
the exercise has ceased [11] (figure 2, lower panel). Through a
process of trans-signalling involving the ubiquitously expressed
glycoprotein-130 (gp130) IL-6 is able to trigger similar cellular
pathways to the membrane-bound form (which also increases
in skeletal muscle after exercise) in tissues that express little or
no membrane-bound IL-6R (figure 3). Of note, this signalling
mechanism is subject to regulatory control via a soluble
(circulating) form of GP130 (sGP130).
The sIL-6R receptor appears in at least two identifiable
isoformsproteolytically cleaved and differentially spliced
(mRNA). The predominant isoform in plasma of healthy
individuals is derived from proteolytic cleavage (>99%) and
although both forms increase after exercise, the cleaved form
remains dominant [11]. The formation of the binary complex
(IL-6/sIL6R) substantially extends the plasma half-life of IL-6,
and mathematical modelling suggests that 70% of sIL-6R is
in this form at rest and that the complex increases twofold
after endurance exercise [18]. When thinking about the
inflammatory capacity of IL-6 it is therefore essential to also
consider the effect of the soluble receptor.
Other notable skeletal muscle-derived factors which may
exert indirect influences (by affecting adiposity) on systemic
inflammation are irisin and IL-15 [5]. Irisin is a recently

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Figure 3. Interleukin 6 (IL6) classical and trans-signalling and inhibition

by soluble gp130 (sgp130). (A) Classical signalling: IL6 binds to membranebound IL6R, then IL6/IL6R binds with membrane gp130, resulting in
formation of the active hexamer complex in cells that express both
membrane IL6R and membrane gp130. (B) Trans-signalling: soluble IL6R
interacts with IL6, then IL6/sIL6R bind with membrane gp130, activating
cells that may not express membrane IL6R. (C) Soluble gp130 (sgp130)
inhibition of trans-signalling: IL6/sIL6R binds to sgp130, which prevents
IL6/IL6R binding to membrane gp130. IL6 cannot bind solely to sgp130 in
the absence of sIL6R, thus sgp130 inhibits trans-signalling but not classical
signalling. Reproduced with permission from Ref. [75].

identified myokine which is released into the circulation at

elevated levels after exercise and potentially has significance
for inflammatory meditators because of its capability to trigger
the change of white adipocytes to brite cells (brown-inwhite). The significance of this is that brite cells display
a phenotype similar to that of brown adipocytes which are
metabolically inefficient cells that augment thermogenesis and
energy expenditure. This contrasts with white adipocytes whose
primary function is for the deposition and storage of lipid. Thus,
irisin may be an intermediary through which skeletal muscle
communicates with adipose tissue to regulate thermogenic
programming. Theoretically, this has favourable implications
for energy homeostasis and metabolic regulation.
IL-15 is an additional factor produced in skeletal muscle
in response to contraction which also appears to exert
favourable effects on adiposity. In particular, IL-15 seems
to exert a beneficial influence on abdominal fat with transgenic
overexpression in murine models leading to a reduction in
central adiposity [19]. In humans, circulating IL-15 has been
found to be inversely associated with trunk adipose tissue
mass [20]. Additional research is necessary to determine the
mechanism by which IL-15 affects central adiposity.

Leucocytes
The effects of acute exercise on leucocyte trafficking and function have been investigated extensively. It is widely accepted that
acute exercise increases the number of circulating leucocytes yet
causes a temporary depression on several aspects of immune
cell function. These effects are related to both the duration
and intensity of exertion, with strenuous exercise (prolonged
and/or high-intensity) yielding the most profound effects [21].

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Leucocytes secrete a variety of cytokines (including IL6), which are involved in the activation and regulation of
the immune response. As monocytes are one of the main
sources of IL-6 (as well as other cytokines) in vivo, several
studies have assessed whether monocytes are the source of the
exercise-induced increase in systemic cytokine concentrations.
However, research examining cytokine mRNA expression (IL6, IL-1, IL-1 and TNF-) in peripheral blood mononuclear
cells (monocytes and lymphocytes) in response to acute
moderate-vigorous cycling indicated that this was unlikely to
be the case [22]. These findings were later confirmed by studies
investigating spontaneous (i.e. unstimulated) intracellular
cytokine production from monocytes in response to acute
exercise [23,24]. Other research has also documented no
change in the spontaneous production of a variety of cytokines
(IL-1, IL-2, IL-4, IL-6, IL-10, IFN- and TNF-) from
several leucocyte subsets (granulocytes, lymphocyte subsets
and monocytes) after acute high-intensity cycling [25]. Thus,
although exercise might mobilize distinct populations of
leucocytes that are already expressing cytokines from marginal
pools, unlike skeletal muscle, exercise does not directly
stimulate production of cytokines from leucocytes.
On the other hand, the influence of acute exercise on
stimulated cytokine production from leucocytes has also
received considerable attention. Studies have mainly focused
on monocytes and T lymphocytes because of the important
role that cytokine production from these cells plays in the
orchestration of the immune response. Several studies have
shown that stimulated cytokine production by monocytes (IL6, TNF- and IL-1) and type 1 T lymphocytes (IFN- ), but not
type 2 T lymphocytes (IL-4), is inhibited following strenuous
exercise [23,24,26], suggesting a weakening of cell-mediated
immune responses. In agreement with this, is the emerging
evidence that acute exercise downregulates monocyte toll-like
receptor (TLR) expression [27]. TLRs are triggered by microbial
pathogens (e.g. lipopolysaccharide) as well as endogenous
danger signals (e.g. heat shock proteins), leading to activation of
the antigen-presenting cell (APC), such as the monocyte. This
subsequently leads to activation of the T lymphocyte through
the interactions between major histocompatibility complex
(MHC) class II molecules and co-stimulatory cell surface
molecules (CD80/86) on the APC with the T-cell receptor
and CD28 on the T-cell membrane, respectively. Activation of
this signalling cascade results in the secretion of inflammatory
cytokines. Notably, the upregulation of CD80, CD86, MHC
class II and IL-6 by CD14+ monocytes following activation
with specific TLR ligands is also reduced following strenuous
exercise [28]. Thus, although exercise may impair immune
function and possibly increase the susceptibility to infection,
this appears to be a small price to pay for a reduction in the
inflammatory capacity of the leucocytes.
Mobilization of regulatory T (Treg ) cells (which are a major
source of IL-10) may also be involved in the anti-inflammatory
effects of exercise. Studies addressing the effects of acute exercise
on Treg cells are scarce, however, with the available evidence
documenting contradictory findings [29,30]. Interestingly, a
recent study in a running mice model showed that high but
not moderate-intensity exercise training resulted in increased

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DIABETES, OBESITY AND METABOLISM

circulating Treg cell numbers [31]. This data may suggest that
high-intensity exercise provides a greater anti-inflammatory
stimulus.

Adipose Tissue
Mounting evidence shows an integral role of adipose tissue
in the development of cardio-metabolic disease. Chronic
low-grade inflammation is now understood to be the key
link between adipose tissue, metabolic dysfunction and
disease outcomes with adverse changes in the adipose tissue
proteome underpinning these events [32]. Notably, adipose
tissue has the capacity to produce at least 75 inflammatory
proteins, and with increasing obesity, the infiltration of
macrophages and a change in the macrophage phenotype
(alternatively to classically activated) prompt adverse changes
in the adipose tissue metabolic profile. These changes lead to
a pro-inflammatory and metabolically unhealthy environment
[33] (figure 4). If in abundance this may spill over into the
circulation, resulting in systemic inflammation.
A key trigger of inflammatory events in adipose tissue in
obesity is thought to be adipocyte hypertrophy with cell volume
expansion leading to tissue hypoxia, cellular stress, necrosis and
ultimately tissue macrophage invasion [32]. Large adipocytes
are insulin resistant and hyperlipolytic whilst small adipocytes
are insulin sensitive and metabolically healthy. The location
of adipose tissue also has a key bearing on its metabolic
function with growing evidence showing that the dominant
source of the inflammatory proteins is the visceral site which
accounts for the strong link between central obesity and cardiometabolic disease. A large body of evidence has described
enhanced gene expression and protein content of some proinflammatory molecules in visceral adipose sites compared
with subcutaneous depots [34]. The adverse consequence of
this may be related to the anatomical location of visceral
adipose tissue which directly exposes the liver to a continuous
abundance of fatty acids and pro-inflammatory adipokines.
In healthy weight humans visceral fat accounts for <20%
of total fat in males and significantly less in females [35],
therefore its overall contribution to the chronic inflammatory
state must be aggregated. Usefully, exercise is a potent stimulus
for visceral adipose tissue lipolysis and reductions in central
adiposity have been shown to occur with exercise training
independent of overall weight change [36]. This indirect

Figure 4. The metabolic and inflammatory profile of adipose tissue with

perturbations in energy balance. Changes in adiposity resulting from weight
loss or gain lead to alterations in the production of inflammatory proteins,
macrophage phenotype, and chemokines and lymphocytes.

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influence may represent one important mechanism by which

exercise favourably impacts systemic inflammation.
Information concerning the direct effects of acute exercise on
adipokine secretions is sparse; however, some information is
available regarding the effects on IL-6, leptin, adiponectin,
resistin and TNF- [37]. In contrast to skeletal musclederived IL-6 the literature is consistent in stating that the
release of IL-6 from adipose tissue is suppressed during lowintensity prolonged exercise, although levels may increase after
exercise [38]. It is possible that this adipose-derived IL-6 may
mediate lipolysis and fat metabolism in the recovery period
after exertion. A recent study has highlighted the centrality
of IL-6 in mediating an anti-inflammatory influence within
subcutaneous adipose tissue in response to acute exercise [39].
Specifically, the capacity of exercise to suppress leptin and
TNF- mRNA within subcutaneous adipose tissue (as seen in
wild-type rodents) was absent in a rodent model with global
IL-6 knockout.
Resistin and TNF- are proteins produced within the nonadipocyte fraction within adipose tissue that are known to exert
potent pro-inflammatory actions. Resistin was identified as an
adipokine directly linked to the induction of insulin resistance
in several animal models [40] with research describing negative
effects on glycaemic control and cardiovascular function via
adverse effects within the liver, adipose tissue and vasculature.
Similarly, the primary characteristic of TNF- is its negative
impact on insulin action and glucose metabolism through
impairing insulin signalling within skeletal muscle and adipose
tissue [32]. A handful of studies have assessed the acute impact
of exercise on circulating levels of resistin and TNF-. The consensus of evidence suggests that acute exercise has no impact
on circulating TNF- [37]. Similarly, despite notable improvements in insulin sensitivity occurring in response to single bouts
of continuous-moderate-intensity cycling, circulating levels of
resistin remain unchanged [41]. These data suggest that shortterm improvements in insulin action after single episodes of
exercise are not mediated by TNF- or resistin.
Leptin and adiponectin are proteins produced primarily by
adipocytes with circulating levels, correlating positively and
negatively with adipose tissue mass, respectively. Leptin was
identified as a key regulator of energy balance but is now also
recognized as a key mediator of immune function. Leptin has
potent pro-inflammatory actions influencing both the innate
and adaptive immune systems, and heightened levels seen in
obesity contribute to systemic inflammation [42]. The impact
of exercise on circulating leptin has received significant attention with the consensus of evidence, suggesting that circulating
levels remain stable during acute exercise. An exception to this
may occur when the exercise volume and associated energy
expenditure are substantial (>3348 kJ) whereby reduced
circulating levels may be seen [43]. This change may represent
a compensatory response to the energy deficit but may have
consequences for the inflammatory response.
Adiponectin is one of the most highly abundant plasma
proteins [44]. Plasma adiponectin is positively related to
insulin sensitivity and glucose tolerance which is mediated via
favourable effects on skeletal muscle glucose uptake, fatty acid
oxidation [45] and hepatic gluconeogenesis [46]. Circulating

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levels of adiponectin have been measured in response to acute
exercise to determine whether changes in adiponectin are
related to transient exercise-induced improvements in insulin
sensitivity. Data suggest that changes in adiponectin are not
related to improved insulin action in response to acute exercise
as neither moderate or high intensity continuous aerobic
exercise affect circulating levels of adiponectin [47,48].

The Effect of Repeated Bouts of Physical

Activity (Training) on Chronic Low-grade
Inammation
The evidence to support a beneficial role of physical activity
on chronic low-grade inflammation is essentially derived from
two sources: large cohort studies or intervention studies. A
comprehensive review of this literature has been compiled
by Beavers et al. [3]. Both types of studies are confounded
by the difficulty of introducing a single intervention, that
is, physical activity. In many, therefore, the concept is more
accurately described as the introduction of a lifestyle change
in which motivation of the participants not only leads to an
increase in physical activity but also frequently causes dietary
changes. This behaviour modification confounds the data in
terms of identifying the main driver of physiological change.
Additionally, the lifestyle modification may also reduce body
fat, the principle source of the inflammatory proteins. It is
possible, however, to account, at least in part, for these factors
in the subsequent analysis of the data and after adjustment
large cohort studies consistently show an inverse association
between physical activity and chronic low-grade inflammation.
The impact of physical activity is most evident when it is more
frequent and more intense [49,50].
The most common biomarker measured in large cohort
studies to reflect inflammatory status is CRP, probably because
of its widespread clinical use. CRP is an acute phase reactant
that is a non-specific marker of systemic inflammation and
has been implicated in the pathogenesis of several chronic
conditions, most notably coronary heart disease (CHD).
Considerable evidence from epidemiological and experimental
studies has identified CRP as a marker of CHD risk with
useful prognostic capacity in primary and secondary CHD
prevention. A large collection of studies have consistently
reported inverse associations between self-reported physical
activity or objectively measured aerobic fitness with circulating
levels of CRP [51]. The effect of focused interventions is
less clear, however, which is most likely because of marked
differences in study protocols and other confounding outcomes
such as weight loss.
Although CRP is the most common measure in many of
these studies, other biomarkers, particularly IL-6 and TNF-,
are increasingly being reported to be inversely associated with
physical activity [3]. The majority of the large cross-sectional
cohort studies are limited, however, owing to the inability to
capture objective physical activity data leading to participant
misclassification. Moreover, although large cohort studies provide valuable insight into associations between physical activity
and a number of variables, direct causation can never be proven.
In an attempt to overcome these issues, studies have used an

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intervention model and in these studies the evidence for the
benefits of physical activity on chronic low-grade inflammation
is less consistent. This is possibly because of under-powering
of studies and to diversity in terms of the types of interventions
imposed. The following analysis of interventions therefore
attempts to categorize different exercise strategies.

Sedentary Behaviour
Recently, interest has ignited around sedentary behaviour, a
new physical activity paradigm which stresses the negative
health implications of too much time spent sitting or lying
[52]. The major stimulus for this research derives from
animal studies which have shown that experimental muscle
unloading negatively impacts lipoprotein lipase activity and
lipid metabolism [53]. The important distinction in this field
is that the adverse health outcomes of sedentary behaviour
are independent of moderatevigorous physical activity [54].
Emerging research has indicated that sedentary time is
positively associated with elevated inflammatory proteins
[55,56] with one report suggesting that the association
may be stronger in women than in men [57]. At present,
no interventions have been implemented to assess the
impact of reducing sedentary time on systemic inflammation.
Our research group is currently conducting a randomized
behavioural intervention (project STANDSedentary Time
ANd Diabetes) examining the health impact of reducing
sedentary time in young adults at risk of T2D [58]. This
study will provide detailed information regarding the effects of
reducing sedentary time on candidate inflammatory markers
in an at risk population.

Low to Moderate Intensity Continuous Exercise

Walking has been suggested to be the most likely form of
exercise to increase physical activity as it is accessible to all,
poses little risk of injury, and can be accumulated into daily
routine [59]. A study conducted by our own group investigated
the effectiveness of a community-based walking intervention
on systemic inflammatory proteins in overweight middle-aged
men and women in Scotland [60]. In this study, there was no
attempt to change any other lifestyle factors and the control
group was given exactly the same support but was delayed in
starting their walking intervention. The study concluded that
although all participants achieved the physical activity targets
(an increase of 3000 steps/day, at least 5 days/week), which were
the physical activity guidelines at the time, the intervention
brought no improvements in CRP, IL-6, sIL-6R, TNF- or
soluble TNF receptors I and II (sTNFR1 and sTNFRII). This
was the first study to undertake an exercise intervention in a
community setting using the public health guidance.
This finding of no change to inflammatory markers after a
low-intensity exercise intervention was reproduced by Polak
et al. [61] who observed no change in circulating inflammatory
proteins (IL-6, TNF- and adiponectin) following a period of
low-intensity cycling. Additionally, after a 12-week moderateintensity aerobic exercise intervention Christiansen et al. [62]
did not see any changes in circulating inflammatory proteins

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DIABETES, OBESITY AND METABOLISM

(IL-6, IL-15, IL-18, MCP-1, MIP1 and adiponectin). This

was despite witnessing favourable changes in the adipose tissue
gene expression of some inflammatory markers.
Thompson et al. [63] examined the impact of a higher
intensity exercise intervention in a group of middle-aged
sedentary men over the course of 6 months. In this study,
aerobic exercise at 5070% of maximum aerobic capacity
(3060 min/day) induced a reduction in circulating IL-6 but
had no influence on CRP or soluble intercellular adhesion
molecule 1 (ICAM-1)a vascular adhesion molecule used as
a biomarker for endothelial dysfunction. Uniquely this study
also followed participants through a 2-week detraining period
and documented a reversal of circulating IL-6 to pretraining
levels, pointing to a direct influence of training.

Resistance/Combined Aerobic and Resistance Training

Although the majority of studies have investigated aerobic
exercise training, resistance exercise interventions have been
shown to attenuate systemic inflammation by reducing
circulating levels of CRP and increasing levels of adiponectin
[64]. Additional research suggests that a combination of
aerobic and resistance exercise training may confer the
greatest favourable impact on systemic inflammation [65,66].
Specifically, in a sample of patients with T2D or the
metabolic syndrome, Balducci et al. compared the impact
of aerobic exercise (low- and high-intensity conditions)
and combined aerobic and resistance exercise training on
markers of inflammation and observed beneficial changes in
pro-inflammatory molecules with high-intensity aerobic, and
combination training (leptin, IL-6 and resistin), independent
of weight change [66]. Notably, additional improvements (IL1b, TNF- and IFN ) including changes in anti-inflammatory
factors (IL-4 and IL-10) were only witnessed in the combination
training group. These data may suggest that the greatest benefits
of exercise are realized when both forms of training are
undertaken. Such inferences are congruent with other data
which have demonstrated the utility of integrated lifestyle
interventions (diet and exercise) that have included both
aerobic and resistance training elements [67].

High-intensity Intermittent Exercise

Striking health improvements, most notably enhanced insulin
sensitivity, have been found with a novel form of exercise which
involves intermittent bouts of high-intensity exercise [68]. This
form of exercise training has been termed HIIT and several
studies have shown that this form of training can yield rapid
health improvements over the course of just 2 weeks (three
training sessions per week) [68]. Utilizing this form of exercise
training within a sample of inactive overweight/obese men,
our own group has been able to detect significant changes in
the circulating and adipose tissue IL-6 system, with decreased
sIL6R observed after training in the former, and reduced IL-6
but increased IL-6R in the latter (figure 5) [69]. Moreover,
within the circulation, levels of MCP-1 and adiponectin were
also reduced following HIIT whilst the concentrations of TNF, IL-6, ICAM-1 and IL-10 remained unchanged. Within

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Figure 5. Interleukin-6 and sIL-6R in the circulation (top panel) and adipose tissue (lower panel) at pre- and post-2-weeks HIIT in overweight and obese
males, mean (s.e.m.) (n = 12) *Significantly different to pretraining (p < 0.05). Adapted with permission from Ref. [69].

adipose tissue, concentrations of ICAM-1 remained unchanged

whilst TNF-, IL-10 and MCP-1 were undetectable. These data
suggest that 2 weeks of HIIT is sufficient to induce some
beneficial alterations in the resting inflammatory profile of an
overweight and obese male cohort.
The necessity for exercise to be of high intensity to reduce
the risk of chronic cardiovascular and metabolic diseases
via its anti-inflammatory effects is supported by a running
mouse model, where the responses of circulating Treg cells
to moderate and HIIT were examined [31]. Only the highintensity training resulted in increases in Treg cell numbers with
reduced pro-inflammatory and increased anti-inflammatory
cytokine expression. Thus, if the total energy expenditure of
exercise is held constant, exercise performed at a vigorous
intensity appears to convey greater metabolic health benefits
than exercise of a moderate intensity.

Overtraining
In contrast to the previous descriptions of exercise, an
excessive volume of activity without sufficient opportunity for
rest can induce deleterious health and performance effects,
a phenomenon which has been termed the overtraining
syndrome [70]. This feature is typically witnessed only in
athletes undergoing an intensified period of training without
sufficient rest and is characterized by weight loss, malaise,
mood/sleep disturbances, chronic fatigue and impaired athletic
performance. The aetiology of this syndrome is not fully

Volume 15 Suppl. 3 September 2013

understood but is thought to be at least partly mediated

by low-grade systemic inflammation [71]. Notable features
of this are augmented circulating levels of pro-inflammatory
cytokines (TNF-, IL-6 and IL-1b) which act on the brain to
induce sickness-like behaviours including anorexia, depression
and sleep disturbance [71].
The role of IL-6 as a mediator of the overtraining syndrome
has received greater attention than other cytokines. In various
clinical settings IL-6 has been found to relate to fatigue
symptoms. Robson-Ansley et al. have also described heightened
circulating IL-6 concentrations in a group of male triathletes
subjected to an intensified period of exercise training which
was associated with sensations of fatigue and malaise [72].
Not all studies have reproduced this finding, however, and
given the relatively sparse amount of data available on this
issue the contribution of IL-6 to the overtraining syndrome
remains uncertain. Recently it has been suggested that the
sIL-6R may link IL-6 with the overtraining syndrome through
the potentiation of the brains responsiveness to IL-6 [73]
and circulating sIL6R levels have been found to increase
significantly during a 6-day mountain bike endurance event
(468 km) with levels correlating positively with daily fatigue
scores [74]. Additional research is needed to fully characterize
the role of cytokines and the IL-6 system as orchestrators of the
overtraining syndrome.

doi:10.1111/dom.12156 57

review article
Conclusions and Recommendations

DIABETES, OBESITY AND METABOLISM

References

A large and consistent body of evidence suggests that single

bouts of physical activity induce an anti-inflammatory environment. This response is most vividly represented by a marked
increase in the circulating levels of skeletal muscle-derived IL-6
which triggers beneficial changes in the circulating levels of several other inflammatory mediators. The amount of IL-6 released
is dependent upon the mass of muscle recruited, the intensity
and duration of the exercise and is related (inversely) to the
glycogen status of the muscles. Accordingly, to promote an antiinflammatory environment through physical activity it would
be logical to speculate that the optimal regimen to adopt would
be whole body running or rowing (as opposed to cycling, where
the upper body is relatively passive). Physical activity should
be of a sufficient intensity to utilize glycogen as its primary fuel
(greater than 70% of maximum aerobic capacity) and/or of
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cause any adaptive changes and it is not until the activity is
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Data from intervention studies suggest that accumulated
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that is, moderatevigorous intensity (at least 70% of maximum
aerobic capacity). A combination of aerobic activities with
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likely yield the greatest benefit, particularly with regards to
optimizing the anti-inflammatory effect of training. Although
further clarification is required, emerging data suggest that
HIIT may offer a powerful stimulus to confer notable beneficial
inflammatory changes with improvements being obtainable
within a short period of time (within 2 weeks). Individuals
performing excessive amounts of physical activity (typically
athletes) should be vigilant of symptoms representative of the
overtraining syndrome and careful planning of recovery and
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