Review Article: Adipo-Myokines: Two Sides of The Same Coin-Mediators of Inflammation and Mediators of Exercise

Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2013, Article ID 320724, 16 pages
http://dx.doi.org/10.1155/2013/320724
Review Article
Adipo-Myokines: Two Sides of the Same CoinMediators of
Inflammation and Mediators of Exercise
Silja Raschke and Jrgen Eckel
German Diabetes Center, Paul-Langerhans-Group of Integrative Physiology, Auf m Hennekamp 65, 40225 Dusseldorf, Germany
Correspondence should be addressed to Jurgen Eckel; [email protected]
Received 26 February 2013; Revised 29 April 2013; Accepted 7 May 2013
Academic Editor: Daniel Konrad
Copyright 2013 S. Raschke and J. Eckel. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
This review summarizes the current literature regarding the most discussed contraction-regulated moykines like IL-6, IL-15, irisin,
BDNF, ANGPTL4, FGF21, myonectin and MCP-1. It is suggested that the term myokine is restricted to proteins secreted from
skeletal muscle cells, excluding proteins that are secreted by other cell types in skeletal muscle tissue and excluding proteins which
are only described on the mRNA level. Interestingly, many of the contraction-regulated myokines described in the literature are
additionally known to be secreted by adipocytes. We termed these proteins adipo-myokines. Within this review, we try to elaborate
on the question why pro-inflammatory adipokines on the one hand are upregulated in the obese state, and have beneficial effects
after exercise on the other hand. Both, adipokines and myokines do have autocrine effects within their corresponding tissues. In
addition, they are involved in an endocrine crosstalk with other tissues. Depending on the extent and the kinetics of adipo-myokines
in serum, these molecules seem to have a beneficial or an adverse effect on the target tissue.
1. Skeletal Muscle and Adipose Tissue as

Endocrine Organs
In line with the acceptance of adipose tissue as an endocrine
organ [13], path-breaking work during the last decade
demonstrated that skeletal muscle is an active endocrine
organ releasing myokines, which might in part be responsible for the beneficial effect of exercise [46]. These
myokines are described to communicate with cells in an
autocrine/paracrine manner, locally within the muscles, or in
an endocrine fashion to distant tissues.
Obesity in a combination with a lack of exercise is a strong
risk factor to develop metabolic diseases and type 2 diabetes.
Physical inactivity causes the accumulation of visceral fat and
the health consequences of both are related to systemic lowgrade inflammation [7, 8]. Adipocytes from obese patients
are characterized by altered endocrine function, leading to
increased secretion of proinflammatory adipokines, such as
TNF, chemerin, MCP-1, dipeptidyl peptidase 4 (DPP4), and
others [914]. Thus, the dysregulation of adipokine secretion
is related to metabolic diseases. The activation of inflammatory pathways leads to insulin resistance in peripheral tissues
such as skeletal muscle and adipose tissue itself, constituting

an early defect in the pathogenesis of type 2 diabetes [15].
Different research strategies revealed the complexity of the
adipocyte secretome, and to date more than 600 potentially
secretory proteins were identified [2].
In addition, it is well accepted that contracting skeletal
muscle secretes enhanced levels of myokines which have a
beneficial endocrine effect on other organs, presenting novel
targets for the treatment of metabolic diseases and type 2
diabetes [16].
2. Identification of Contraction-Regulated
Myokines
It is well accepted that physical activity exerts multiple beneficial effects on the prevention of chronic diseases, both due to
an improved energy balance and due to effects independent
of obesity. It is assumed that contraction-regulated myokines
play a pivotal role in the communication between muscle and
other tissues such as adipose tissue, liver, and pancreatic cells
[1618].
Table 1: Contraction-regulated myokines. A search of original articles in pubMed was performed for all myokines described to identify
contraction regulation of a myokine on the level of enhanced muscle mRNA expression and enhanced serum level. In addition, studies
describing basal secretion of the indicated myokine from myotubes (in vitro studies) are given. The search terms used were skeletal muscle,
myokine, exercise, secretion, and the indicated myokine. Reference lists of identified articles were also used to search for further papers.
Myokine
ANGPTL4
BDNF
FGF21
FSTL1
IL-6
IL-7
IL-8
IL-15
Secreted by cells
Enhanced muscle mRNA

level after exercise
Enhanced serum
level after exercise
[157]
n.d. [19]
[79]
[112, 113]
[24]
[159]
[140]
[32]
[19]
[31]
[158]
[159]
[51, 70, 160, 161]
[48, 52, 55]
[47]
[75]
[63, 64]
[83]#
[112]
[35]
[4951]
[52, 165]
[55, 57]
[56]
[32, 69]
[86]
[88]#
[173]#
n.d. [162164]
[55]
Irisin
LIF
MCP-1
[166]
[68, 140]
[166, 167]
[70, 72]
Myonectin
[86, 87]
[86]
Myostatin
PAI-1
[147]
[31]
[168172]#
[31]
PEDF
[31]
[31]
VEGF
[24]
[174]
[51]
: secretion, enhanced muscle mRNA level, or serum level of myokines have been shown in indicated publications. : contraction regulation of myokine has
not been shown. # Myokine serum levels are described to be decreased after exercise, n.d.: not detected in supernatants of myotubes.
Research of the last decade revealed that several

myokines are regulated by contraction, like angiopoietin-like
4 (ANGPTL4), brain-derived neurotrophic factor (BDNF),
fibroblast growth factor (FGF) 21, follistatin-like 1 (FSTL1),
interleukin (IL)-6, IL-7, IL-15, irisin, leukemia inhibitory
factor (LIF), myonectin, myostatin, and vascular endothelial
growth factor (VEGF) (for references see Table 1). For
some of these reported myokines, the description as a
myokine is based on mRNA data of skeletal muscle biopsies.
For example, Matthews et al. [19] report increased BNDF
mRNA level in human contracting skeletal muscle biopsies.
Although the authors could prove enhanced serum levels
after exercise in humans and increased BDNF protein level
after electrical pulse stimulation of C2C12 cells, BDNF basal
secretion could not be detected in the media from skeletal
muscle cells in vitro [19]. Secretion is the critical characteristic
of a myokine and it is preferable to restrict the term myokine
to those proteins that are released by skeletal muscle cells
themselves.
Nevertheless, the term myokine has also been employed
to describe a protein that is synthesized by skeletal muscle
tissue, rather than by the skeletal muscle cell. The initial
characterization of a candidate myokine is frequently the
detection of the gene expression in skeletal muscle tissue by
mRNA expression or immunodetection of protein lysates.
One dilemma in only determining gene expression or protein
level in skeletal muscle biopsies is that aside from skeletal
muscle fibres, skeletal muscle contains extended layers of

connective tissues, capillaries, and nerve cells among others.
Thus satellite cells, endothelial cells, fibroblasts, and motor
neurons are included in the analysis. Gene expression must
be followed by the detection of the encoded protein in skeletal
muscle fibers. Additional immunostaining of the skeletal
muscle tissue sections shows that the protein production
is indeed intramyocellular. When the expression is first
identified in skeletal muscle tissue, the validation of a protein
as a myokine has to include that secretion from skeletal
muscle cells is demonstrated. In practice, this will generally
reflect selective release from skeletal muscle cells in vitro
either by the use of primary human or animal skeletal muscle
cells or from clonal cell lines. Equally, proteins that have been
identified in skeletal muscle cells needs to be verified for
the native tissue. We recommend that the term myokine is
used for a protein that is synthesized and secreted by skeletal
muscle cells.
The identification of a protein as a contraction-regulated
myokine represents an additional critical step in the analysis.
Repeated biopsy sampling from one muscle is necessary to
investigate muscular adaptation to different forms of exercise.
The adaptation is thought to be the result of cumulative
effects of transient changes in gene expression in response
to single exercise bouts. Nevertheless, it was shown that
multiple fine needle biopsies obtained from the same muscle
region can per se influence the expression of marker genes
induced by an acute bout of resistance exercise [20]. Thus,
repeated biopsies have to be taken carefully in regard to
avoiding an inflammatory response in the tissue. In the
case that contraction regulation of a protein is first identified in muscle biopsies on the mRNA level, it is essential
to determine whether the enhanced mRNA expression is
translated to enhanced protein level. An additional elegant
approach is to induce contraction of human skeletal muscle
cells or clonal cell lines by electrical pulse stimulation [21
24]. The potentially contraction-regulated myokine can be
analyzed on the mRNA and protein level. Most importantly,
enhanced secretion can be determined in the supernatants by
immunodetection.
3. Secretome of Muscle Cells

To gain a broader view, recent efforts have focused on
exploring the complete secretome of skeletal muscle by
proteomic studies. New technological advances, like array
studies and proteomic analysis, made the analysis of the
qualitative and quantitative analysis of the secretome of
skeletal muscle possible. These approaches extended the list of
described myokines rapidly. Chan et al. and Henningsen et al.
have investigated altered regulation of secretome components
at different time points of muscle differentiation of murine
C2C12 cells by a quantitative proteomics approach [2527],
while Yoon et al. have studied the regulation of myokine
secretion by rat skeletal muscle cells after insulin stimulation
[28] and TNF treatment [29]. Recently, Hittel et al. have
explored the secretome from cultured myotubes derived
from extremely obese compared with healthy nonobese
women [30]. All these studies found hundreds of secreted
proteins from skeletal muscle, some regulated by insulin
or TNF, others during differentiation. A drawback of all
these studies is the use of noncontracting cells although
contraction is a major characteristic of skeletal muscle activating intracellular signalling pathways, changing the secretory profile, inducing metabolic adaption and the change
of its plasticity. To overcome this problem, Norheim et al.
combined the proteomic analysis of the secretome of human
myotubes with mRNA expression data of muscle biopsies
in response to strength training. Using this approach the
authors identified 15 novel contraction-regulated myokines
[31]. Recently, Catoire et al. described the effect of endurance
exercise on gene expression in exercising and nonexercising
human muscle by one-legged cycling [32]. Noticeably, acute
exercise also caused substantial gene expression changes
in nonexercising leg [32]. This effect might be mediated
by changes in circulating factors such as free fatty acids,
adrenalin, and lactate, but might also support the myokine
concept.
Nevertheless, all these studies indicate that skeletal muscle cells are, like adipocytes, major secretory cells. Clustering
these skeletal muscle-derived proteins according to their
postulated function revealed that these myokines can be
sorted to several groups, including myokines contributing
to energy metabolism, angiogenesis, blood vessel regulation,
and myogenesis [33].
4. IL-6: The Best Characterized Myokine

Some of the first reports in this research field identified
IL-6 as a secreted protein from skeletal muscle [34, 35].
The identification that contracting human skeletal muscle
releases significant amounts of IL-6 into the circulation
during prolonged single-limb exercise was a milestone in this
research field and identified skeletal muscle as an endocrine
organ [36]. Up to now, IL-6 is the most prominent musclederived protein, which was demonstrated to be upregulated
in plasma after exercise without muscle damage [34, 37].
The level of circulating IL-6 increases in an exponential
fashion in response to exercise [36, 38, 39] and declines in
the postexercise period [40]. The magnitude by which plasma
levels increase is related to exercise duration, intensity, and
the muscle mass involved in the mechanical work [36, 38, 39,
41]. However, during one year of training intervention plasma
levels of IL-6 remained unchanged [42]. Plasma IL-6 levels
can increase up to 100-fold in response to exercise although
less strong effects are more frequent [43]. In addition to
human serum and skeletal muscle biopsy data, IL-6 has been
shown to be secreted by primary human skeletal muscle
cells in vitro and its secretion was increased by contraction
[24].
5. IL-15: A Contraction-Regulated Myokine?

IL-15 is discussed as a contraction-regulated myokine in
the literature which may play a role in muscle-fat crosstalk
[44, 45] mediating some of the beneficial effects of physical
activity [46]. Until today, five groups analyzed the regulation
of IL-15 after different exercise protocols in humans. However, conflicting data are published whether physical activity
affects IL-15 expression, protein level, and secretion from
skeletal muscle.
In a first report, no change in IL-15 mRNA level was
described in human vastus lateralis muscle biopsy samples,
which were taken immediately after 2 h intensive resistance
training [47]. Although, Nielsen et al. observed that IL-15
mRNA content was upregulated twofold in human vastus
lateralis muscle 24 hours following a single bout of resistance
exercise, this increase in mRNA level was not accompanied
by an increase in muscular IL-15 protein level or plasma IL-15
[48]. In addition, Riechman et al. demonstrated that immediately after the end of one resistance exercise bout, plasma
IL-15 increased slightly (approximately 5%) [49]. Recently,
it has been shown that 30 min treadmill running at 70%
of maximum heart rate resulted in a significant increase in
circulating IL-15 level in untrained healthy young men (about
12%), measured 10 min after exercise [50]. Different from
these acute exercise studies, Yeo et al. described that both
8-week moderate- and high-intensity resistance exercises
enhanced IL-15 serum levels [51]. In this study, the authors
showed that IL-15 blood level was significantly enhanced after
8 weeks of moderate intensity resistance exercise (250%),
while the increase of the myokine prototype IL-6 was rather
small (115%). High intensity resistance training also enhanced
IL-15 blood levels, but to a lower extent (150%).
4
In addition, training studies were performed in mice and
rats. It has been shown that IL-15 mRNA expression in soleus
and gastrocnemius muscle is increased after 8-week treadmill
running training in rats, while plasma IL-15 level was not
changed [52]. Yang et al. observed about 1.7-fold increase
in IL-15 mRNA expression after three weeks of free wheel
running in mice but did not analyze protein or serum level.
Nevertheless, while the observed increase in plasma IL-15
levels in humans is rather small (512%) after acute exercise
and not depending on the mode of exercise, particularly
moderate intensity resistance exercise had a significant effect
on IL-15 blood levels. However, to the best of our knowledge,
secretion of IL-15 from muscle cells has not been described
yet, and it has not been shown that the observations on muscle mRNA level are translated to meaningful contributions to
IL-15 serum levels.
6. Irisin: A Novel Myokine

Just recently, a novel identified myokine has drawn the
attention as a novel preventive and therapeutic target to
treat obesity and metabolic diseases like type 2 diabetes.
Bostrom et al. observed that overexpression of PGC1 in
mice muscle as well as exercise induces the expression of
the FNDC5 (fibronectin type III domain containing protein
5) gene, a gene which has scarcely been studied before.
FNDC5 is described as a protein containing a signal peptide, fibronectin type III repeats, and hydropathy analysis
revealed a hydrophobic region, which is likely to encode a
transmembrane domain. Previous studies linked the gene
to differentiation of myoblasts and neurones [53, 54], and
it has been suggested that FNDC5 is located in the matrix
of peroxisomes [53]. Bostrom et al. described that the Cterminal tail of the protein is located in the cytoplasm,
whereas the extracellular N-terminal part is supposed to
be cleaved and released as novel messenger molecule called
irisin [55]. Mice subjected to three weeks of free wheel
running showed enhanced muscle mRNA expression and
elevated irisin plasma concentrations (65%). In addition, ten
weeks of supervised endurance exercise training revealed a
twofold increase in circulating irisin levels compared to the
nonexercised state in a cohort of older subjects [55]. Both
the mice and human study analyzed the long-term effect
of exercise on irisin plasma levels. It is not described if
enhanced serum levels of FNDC5 after muscle contraction
are dependent on enhanced gene expression or dependent on
enhanced cleavage of the membrane protein.
However, using gene-chip probe sets Timmons et al.
observed no effect on FNDC5 mRNA level neither after
6 weeks of intense endurance cycling in younger subjects
nor after supervised resistance training [56]. Timmons et al.
demonstrated that FNDC5 induction in muscle occurred
only in highly active elderly subjects compared to sedentary
controls (1.3fold), which were a minority of analyzed subjects.
They failed to confirm FNDC5 gene expression by aerobic
exercise in younger subjects. Huh et al. observed minor
effects on irisin plasma levels after 1 week of exercise (increase
of about 18%) and no effect after prolonged training over
8 weeks [57]. Up to now, there is only one study showing
a robust activation of FNDC5 after exercise in humans
measured by RT-PCR in muscle biopsies [24], however,
limited to a very small number of subjects.
Although Bostrom et al. described the discovery of the
novel myokine irsin, the authors showed that the release of
irisin exclusively in HEK 293 cells transfected with a vector
expressing FNDC5 followed immunodetection of culture
media protein. It has not been confirmed that muscle FNDC5
mRNA is translated to protein in primary or clonal skeletal
muscle cells, and, most importantly, it has not been shown
that irisin is secreted from skeletal muscle cells. Furthermore,
to demonstrate the secretion of irisin from HEK293 cells
and to analyze murine and human serum samples, the
authors used an antibody, which most likely cannot detect
the cleaved irisin, since the antibody used is directed against
the C-terminal part of the protein (Abcam 149178, Cterminal) [58]. Taken together, future studies should address
FNDC5/irisin precise expression and cleavage mechanism to
clarify the controversy of current literature.
7. BDNF: Released from the Muscle or

the Brain?
BDNF belongs to the family of neurotrophins (NT), which
includes nerve growth factor, BDNF, NT-3, NT-4/5, and NT6. These proteins are produced as large precursor proteins
that are then cleaved to form the mature neurotrophic protein
(reviewed in [59]). In the literature BDNF is discussed
as a contraction-regulated myokine [6]. During myogenic
differentiation, the expression of BDNF is drastically reduced
and is hardly detectable in adult rat skeletal myofibers
[60]. By reverse transcription PCR, in situ hybridization,
and immunofluorescence, it was shown that BDNF is not
expressed at significant levels within mature myofibers [60].
In situ hybridisation analysis revealed that in adult rat muscle
the constitutive expression of muscular BDNF is confined to
the myofibres. Satellite cells, Schwann cells, endothelial cells,
fibroblasts, or axons did not appear to contribute to BDNF
production in normal muscle [61]. In complementary cell
culture experiments, it has been shown that levels of BDNF
correlate with the population of satellite cells [60]. BDNF is
required for early phases of myogenic differentiation, which
is delayed in the absence of BDNF [62]. Nevertheless, BDNF
protein level was determined in lysates of rat L6 cells [60] and
murine C2C12 cells [19].
Serum BDNF levels increased after a graded cycling exercise test in humans (30%) [63] and at the point of exhaustion
at the end of a ramp test (about 25%) [64]. Matthews et al.
reported enhanced BDNF mRNA and protein expression in
human skeletal muscle and after bicycle exercise [19]. Cell
culture experiments using murine C2C12 cells stimulated
by electrical pulse stimulation confirmed that contractile
activity enhanced BNDF mRNA and protein level. Although
Matthews et al. report increased serum levels after exercise
in humans, BDNF basal secretion by C2C12 that underwent
contraction has not been proven and overexpression of BDNF
in mouse skeletal muscle did not lead to differences in plasma
BDNF [19], leading the authors to the conclusion that BNDF
exerts its action locally and is not released into the circulation.
Matthews et al. reported an autocrine effect of BNDF since
treatment of skeletal muscle cells with recombinant BDNF
resulted in enhanced phosphorylation of AMP-activated
protein kinase (AMPK) and ACC in rat L6 cells which leads
to enhanced fatty acid oxidation [19].
In mice, treadmill exercise induced an increase in BDNF
mRNA expression in the hippocampus and cortex (threeto fivefold) [65]. In humans, a BDNF release from the
brain was observed at rest and increased two- to threefold
during exercise. Both at rest and during exercise, the brain
contributed 7080% of circulating BDNF [65]. These results
suggest that the brain is a major, but not the sole contributor
to circulating BDNF after exercise.
8. MCP-1
MCP-1 is a chemokine and member of the small inducible
cytokine family. It plays a crucial role in the recruitment of
monocytes and T lymphocytes into tissues [66, 67]. MCP1 was detected in supernatants of C2C12 cells [68]. In mice,
plasma IL-6 levels were markedly increased 3 h following
maximum progressive swimming, while MCP-1 plasma levels
were not altered by exercise [69]. However, a single bout of
intense resistance exercise increased MCP-1 mRNA expression in muscle biopsy samples obtained from vastus lateralis
muscle about 35-fold after two hours. In comparison, IL6 mRNA expression, the myokine prototype, was enhanced
about 400-fold [70]. One bout of moderate-intensity cycle
exercise increased MCP-1 mRNA levels in vastus lateralis
muscle biopsy samples after 40 min [71]. One-legged cycling
of male subjects induced a significant change in MCP-1
mRNA levels in the exercising leg and enhanced MCP-1
plasma levels after exercise and after 3 hours of recovery [72].
In addition, increased MCP-1 mRNA expression in skeletal
muscle was reported in elderly individuals following one
bout of resistance exercise [73] and in young men after a
repeated eccentric exercise bout [74]. Immunohistochemistry analysis of muscle biopsies colocalized MCP-1 with
resident macrophage and satellite cell populations, suggesting
that alterations in cytokine signalling between these cell
populations may play a role in muscle adaptation to exercise
[74].
9. ANGPTL4: Regulated by Free Fatty Acids

ANGPTL4 represents a prominent long chain fatty acidresponsive gene in human myotubes. Kersten et al. reported
that plasma ANGPTL4 levels in humans increased significantly in response to long-term fasting, chronic caloric
restriction, and endurance training. All these states are characterized by enhanced circulating FFA [75]. Fasting plasma
ANGPTL4 levels of healthy, untrained male volunteers
increased during endurance exercise at 50% VO2 max for 2 h
and especially during subsequent recovery. Importantly, the
increase in plasma ANGPTL4 was abolished when subjects
were given oral glucose, which induces insulin release and
5
thereby suppresses plasma FFA levels [75]. While ANGPTL4
is below the detection limit in supernatants of differentiated
C2C12 cells, long-term treatment of human myotubes (48 h)
with the PPAR-specific activator GW501516 results in the
accumulation of ANGPTL4 in the supernatant [76]. In addition, incubation of human primary myocytes with oleic acid
and linoleic acid enhanced ANGPTL4 mRNA expression.
Nevertheless, this effect was not only observed in primary
human myocytes, but also in FAO hepatoma cells and mouse
intestinal MSIE cells [75].
Catoire et al. have shown in a human one-legged exercise
study that target genes of PPAR transcription factors including ANGPTL4 were induced equally in exercising and nonexercising muscle [77]. Although PPAR is known to be activated by high-intensity exercise [78], Catoire et al. have concluded that the increase of plasma free fatty acid levels due to
acute exercise activates PPARs and therefore ANGPTL4 [77].
Long-term changes in plasma ANGPTL4 levels are most
likely mediated by changes in plasma free fatty acids, which
raise ANGPTL4 gene expression in target tissues. Nevertheless, ANGPTL4 is ubiquitously expressed in human tissues
and highest expression levels were found in liver, followed
by adipose tissue, thyroid, brain, small intestine, and less
in skeletal muscle [75]. Thus, skeletal muscle might not be
the only tissue which is responsible for enhanced ANGPTL4
plasma levels in states of increased FFA levels like endurance
training. Furthermore, ANGPTL4 stimulates adipose tissue
lipolysis, leading to elevation of plasma free fatty acid levels.
Kersten et al. speculated that both mechanisms operate
as a positive feedback loop. Free fatty acids raises plasma
ANGPTL4 and ANGPTL4 raises plasma free fatty acids by
the stimulation of adipose tissue lipolysis [75].
10. FGF21
FGF21 is a member of the fibroblast growth factor super
family, a large family of proteins involved in cell proliferation,
growth, and differentiation. The first evidence that FGF21 is
an Akt-regulated myokine was published by Izumiya et al.
[79]. FGF21 protein expression and secretion are upregulated
by insulin and inhibited by PI3-kinase inhibitor in cultured
C2C12 myocytes [79]. Skeletal muscle mRNA level and
plasma level are induced by hyperinsulinemia studied in
young healthy men during a hyperinsulinemic-euglycemic
clamp [80]. In line with this observation, circulating FGF21
is elevated in impaired glucose tolerance and type 2 diabetes
patients and correlates with muscle and hepatic insulin
resistance [81].
Interestingly, an acute bout of treadmill exercise did
not change FGF21 serum levels in sedentary young women.
However, after two weeks of exercising there was a 1.6-fold
increase in serum FGF21 [82]. In contrast, twelve-week
exercise program combining aerobic and resistance exercise,
five times per week, reduced FGF21 plasma levels in
nondiabetic, obese women (from 230.2 135.9 versus 102.6
117.8 pg/mL) [83]. Nevertheless, nothing is known about the
acute effect of contraction on the expression, protein level,
and secretion of FGF21 from skeletal muscle cells.
11. Myonectin
Myonectin belongs to the C1q/TNF-related protein family
(C1QTNF isoform 5) and shows a sequence homology with
adiponectin in the shared C1q domain, the signature that
defines this protein family [84]. Before myonectin was
described as a myokine, the protein was reported to be
expressed in the retinal pigment epithelium, and mutations in
this gene caused abnormal high molecular weight aggregate
formation, which results in late-onset retinal macular degeneration in humans [85].
Myonectin is supposed to be myokine due to the detection of the myonectin transcript in mice skeletal muscle, with
significantly lower expression in other tissues, immunoblot
detection of myonectin in mouse skeletal muscle lysates [86],
and L6 supernatants [87] as well as induced expression during
differentiation of mouse C2C12 cells [86].
Currently, one human and one mice exercise studies report divergent results regarding the regulation of
myonectin by contraction. Lim et al. reported that a 10week exercise training program in younger and older groups
of healthy women decreased significantly myonectin serum
levels, while training increased VO2 max, mitochondrial
DNA density in skeletal muscle, and plasma adiponectin
levels significantly [88].
On the other hand, free wheel running for two weeks
increased myonectin expression in soleus und plantaris
muscle of mice and circulating serum levels, suggesting a
potential role of myonectin in exercise-induced physiology
[86]. Recombinant myonectin induced the phosphorylation
of AMPK, leading to increased cell surface recruitment of
GLUT4, enhanced glucose uptake, and stimulated fatty acid
oxidation [87]. Thus, enhanced myonectin secretion induced
by contraction could activate signaling pathways providing
enhanced energy demands during contraction.
Most intriguingly, Seldin et al. reported that recombinant
myonectin promotes fatty acid uptake in mouse adipocytes
and rat hepatocytes in vitro by enhancing CD36, FATP1,
and Fabp4 mRNA expressions, which are known to play
important roles in fatty acid uptake. In addition, recombinant
myonectin had no effect on adipose tissue lipolysis [86].
A question that should be addressed by future studies is
why physical activity activates the secretion of a myokine
that induces fatty acid uptake by adipose tissue. Enhanced
myonectin serum levels after exercise would therefore lead
to an endocrine signal that would deplete energy sources
in the blood which is needed by the exercising muscle. On
the other hand, long-lasting increase in myonectin serum
levels could increase fatty acid uptake in adipose tissue and
therefore improve fat metabolism and lipid handling.
12. Adipo-Myokines
In a recently published review, Pedersen and Febbraio suggest that skeletal muscle might mediate some of the wellestablished protective effects of exercise via the secretion of
myokines that counteract the harmful effects of proinflammatory adipokines [6].
Table 1 summarizes the most prominent myokines, which
are described to be contraction regulated. For more than half
of the described myokines, ten out of seventeen, secretion
by adipocytes has also been described (Figure 1). We termed
these cytokines adipo-myokines. How should a cytokine
exert on the one hand inflammatory signalling in the obese
state and have beneficial effects after exercise? Is it likely that
a bidirectional communication between fat and muscle cells
takes place? Just recently, Christiansen et al. reported that
acute exercise increases circulating inflammatory markers in
overweight and obese compared with lean subjects [89]. Why
should inflammatory markers increase after exercise?
13. IL-6: The Prototype Adipo-Myokine

IL-6 seems to be a good example for an adipo-myokine that
is released by both tissues and has the potential to act on
both tissues. As described before, the level of circulating IL6 increases after an acute bout of exercise in an exponential
fashion [36, 38, 39] and declines in the postexercise period
[40].
In addition, the quantitative release from adipose tissue correlates positively with increased body fat content,
which results in systemic elevation of IL-6 plasma levels
[90]. It is overexpressed in human fat cells from insulinresistant subjects [91], increased in the plasma of obese
patients [92, 93], and associated with type 2 diabetes [90,
94], while it was described to be decreased after bariatric
surgery [95]. IL-6 expression was known to be activated
by proinflammatory IKK/NFB signalling pathway which
is thought to contribute to the development of obesityinduced insulin resistance [96, 97]. In addition, it has been
shown to inhibit insulin-signalling pathways in the liver
[98, 99] and adipocytes [91]. In vitro experiments revealed
that IL-6 induced insulin resistance in hepatocytes [99],
adipocytes [91], and in skeletal muscle cells after treatment
with high doses [100]. Incubation of the rat L6 myotubes with
200 ng/mL recombinant IL-6 induced insulin resistance on
the level of diminished Akt phosphorylation after 96 h [101]
and in primary human myotubes after 48 h [100].
Since exercise is thought to increase insulin sensitivity,
the observation that IL-6 is also increased after exercise
seemed quite paradoxical. Interestingly, for skeletal muscle
cells, in vitro studies showed that a rather brief challenge
of minutes to few hours with recombinant IL-6 had a positive autocrine effect on skeletal muscle cells. Recombinant
IL-6 enhanced insulin-stimulated Akt phosphorylation in
primary human myotubes (20 ng/mL) [102, 103] and rat
L6 myotubes (about 200 ng/mL) [101]. In addition, basal
and insulin-stimulated glucose uptake and translocation of
GLUT4 to the plasma membrane were enhanced after 5
120 min in L6 myotubes (1100 ng/mL) [104]. Furthermore,
IL-6 rapidly and markedly increased AMPK and increased
fatty acid oxidation [104, 105]. Interestingly, the regulation of
intracellular signalling mechanisms, mediating IL-6 expression, differs from the classical proinflammatory pathway. IL6 expression in contracting muscle is regulated by c-Jun
terminal kinase (JNK)/activator protein-1 [106] and increases
Myokines
Adipokines
Adipo-myokines
[135]
ANGPTL4
[133, 134]
Adiponec tin
IL-7
[138, 139]
FGF21
[137]
Leptin
[146]
IL-15
[46, 138]
Fstl1
[111]
Resistin
[145]
Irisin
IL-6
[138]
LIF
IL-8
[140]
BDNF
Myonectin
[86]
Secretome studies
[2529, 147, 148]
MCP-1
[12]
Myostatin
(Table 3)
PAI-1
[142]
PEDF
[141]
VEGF
(Table 3)
[143, 144]
Secretome studies
[149156]
Figure 1: Adipokines, myokines, and adipo-myokines. A search of original articles in pubMed was performed for all myokines described in
Table 1 to identify myokines that were also secreted by adipocytes. The search terms used were adipose tissue, adipocyte, and the indicated
cytokine/protein. Reference lists of identified articles were also used to search for further papers. Indicated references published data that the
cytokines/proteins are secreted or not secreted by adipocytes or adipose tissue. No data was published on the secretion of LIF and irisin from
adipocytes or adipose tissue.
insulin-stimulated glucose disposal in humans and glucose

uptake as well as fatty acid oxidation in rat myotubes in vitro
[104].
Although one study reported that acute IL-6 administration in resting healthy young men in physiological
concentrations did not affect whole-body glucose disposal,
net leg-glucose uptake, or endogenous glucose production
[107], some evidence is published that IL-6 might have
systemic effects. IL-6 knock-out mice develop late onset
obesity and impaired glucose tolerance [108]. In healthy
humans IL-6 infusion increases glucose disposal without
affecting the complete suppression of endogenous glucose
production during a hyperinsulinemic-euglycemic clamp
[104]. This insulin-sensitizing effect of IL-6, without influencing glucose output from the liver, indicates that the main
effect of IL-6 on insulin-stimulated glucose metabolism is
likely to occur in peripheral tissues and might just affect
skeletal muscle itself or adipose tissue as well. IL-6 was
described as a potent modulator of fat metabolism in humans,
increasing fat oxidation and fatty acid reesterification without
causing hypertriacylglyceridemia [109]. Infusion of rhIL-6 in
physiological concentrations into healthy humans increased
whole-body fat oxidation [109].
In summary, IL-6 is released by contracting human
skeletal muscle and seems to have a beneficial effect on
insulin-stimulated glucose disposal and fatty acid oxidation
after acute stimulation. These findings support the hypothesis
that the myokine IL-6 is important for muscle metabolism

during contraction, whereas the chronic elevation of IL-6
released from adipocytes may induce insulin resistance. In
addition, Weigert et al. propose a different influence of IL6 depending on the target tissue. In energy-supplying tissues
like the liver and fat the insulin signal is attenuated, whereas
in energy-utilizing tissues like the skeletal muscle insulin
action is improved [102].
14. Follistatin Like 1: An Adipo-Myokine

FSTL1 is the smallest member of the SPARC protein family and a secreted glycoprotein of 4555 kDa that, despite
limited homology, has been grouped in the follistatin family
of proteins. A proteomic approach found FSTL1 in the
supernatant of primary human adipocytes [110]. FSTL1 is
highly expressed and secreted in 3T3-L1 preadipocytes and
dramatically downregulated early in their differentiation to
adipocytes [111]. Nevertheless, subcutaneous white adipose
tissue, lung and heart are the primary sites of FSTL1 transcript expression, compared to brown adipose tissue and
muscle of adult murine tissues [111]. Three proteomics studies
performed in murine C2C12 and rat L6 cell lines identified
FSTL1 as a myokine which is secreted by skeletal muscle
cells [25, 27, 28]. These studies found that FSTL1 is secreted
by murine and rat skeletal muscle cells, and its secretion
is decreased during insulin stimulation and myogenesis.
15. Leptin: An Adipokine rather than

a Myokine
Originally, leptin was described as an adipokine which
controls food intake [115]. It is synthesized and released in
response to increased energy storage in adipose tissue [115
117]. Leptin was detected on the mRNA level in several tissues
including skeletal muscle tissue [118]. Recently, Wolsk et
al. published that human skeletal muscle releases leptin in
vivo [119]. The secretion of leptin from skeletal muscle was
measured by insertion of catheters into the femoral artery
and vein draining the skeletal muscle. The secretion from
adipose tissue was measured by an epigastric vein draining
the abdominal subcutaneous adipose tissue. The authors
measured a leptin release of 0.8 0.3 ng min1 100 g tissue1
from adipose tissue and 0.5 0.1 ng min1 100 g tissue1 from
skeletal muscle. From these results the authors conclude that
the contribution of whole-body leptin production could be
substantial greater than skeletal muscle compared to fat due
to the greater muscle mass in lean subjects. Earlier work
also observed leptin release from human skeletal muscle
tissue and subcutaneous adipose explants, with more than
ten times less secretion from muscle explants compared
to fat explants [120]. Here, we measured the leptin release
of differentiated primary human adipocytes and myotubes.
The myotubes do not secrete leptin or at levels close to
the detection limit (Figure 2). Even in concentrated supernatants of myotubes leptin secretion was barely detectable
and contraction induced by electrical pulse stimulation had
no effect on leptin secretion (Raschke, unpublished observation). Nevertheless, increasing evidence revealed interand intramuscular accumulation of nonmyogenic cell types,
which might contribute to the observed leptin secretion
of skeletal muscle tissue. Preadipocytes of unknown origin
are observed in skeletal muscle [121, 122], and macrophage
50
Myotubes
Adipocytes
40
Leptin secretion (pg/mL)
In addition, Gorgens et al. recently showed that FSTL1 is

also secreted by primary human skeletal muscle cells [112].
Data have shown that FSTL1 is secreted into the media
by cultured C2C12 skeletal muscle cells, and it can directly
act on endothelial cell-signalling pathways that promote
function and survival. FSTL1 overexpression in endothelial
cells was found to enhance endothelial cell differentiation
and migration and diminish endothelial apoptosis [113].
Thus, FSTL1 might be a myokine that mediates some of the
well-established protective effects of exercise that counteract
the harmful effects of proinflammatory adipokines on the
vasculature. In addition, treatment of neonatal rat ventricual
cardiomyocytes with recombinant FSTL1 induced a time- and
dose-dependent increase in AMPK and ACC phosphorylation [114]. Given that FSTL1 mRNA expression was increased
after strength training [31] and after an acute bout of cycling
at 70% VO2 max [112], it might be speculated that exercise
activates FSTL1 expression and secretion in skeletal muscle,
which might act in an autocrine and/or endocrine manner
and activate muscular and/or adipogenic AMPK. However,
the biological role of adipocyte-derived and muscle-derived
FSTL1 has still to be defined.
30
20
10
0
d2
d6
d0
d14
Days of differentiation
Figure 2: Leptin secretion from primary human myotubes and

adipocytes. Primary human skeletal muscle cells and preadipocytes
were differentiated in vitro for 6 and 14 days, respectively. Supernatants were collected on day 2/6 and day 0/14 of differentiation, respectively. Leptin secretion was measured by ELISA (R&D
Systems), 8. Samples were measured according to the
manufacturers instructions.
accumulation is slightly enhanced in skeletal muscle in obese

type 2 diabetic subjects or in elderly individuals [123]. From
the current data, we would conclude that leptin is rather a true
adipokine, instead of an adipo-myokine.
16. IL-15: A Myokine rather than

an Adipokine
Besides BDNF, IL-7, irisin, LIF, and myonectin, IL-15 is a
myokine, which is mainly expressed in skeletal muscle and
not in adipose tissue. The most prominent effect of exercise
on IL-15 serum levels was observed after moderate intensity
resistance training [51]. IL-15 mRNA level in muscle biopsies
taken from marathon runners increased more compared to
other cytokines like IL-6, IL8, and TNF [47]. Most interestingly, it is higher expressed in skeletal muscle compared
to adipocytes [46], while most adipo-myokines are higher
expressed in adipocytes compared to myotubes (Table 3).
Since IL-15 has been described to have anabolic effects, it
may play a role in reducing adipose tissue mass as part of
muscle-adipose tissue crosstalk [124]. In 3T3-L1 adipocytes,
the administration of IL-15 inhibited lipid accumulation
and stimulated secretion of the adipocyte-specific hormone
adiponectin [46]. In addition, IL-15 overexpression in mice
promotes endurance and oxidative energy metabolism and
enhances exercise-related transcription factors in muscle
[125] and most interestingly IL-15 treatment improves glucose
homeostasis and insulin sensitivity in obese mice [126]. In
human subjects, negative correlations between circulating
Table 2: Overview of selected adipo-myokines which are associated with obesity and insulin resistance.
Adipo-Myokine
IL-6
IL-7
IL-8
MCP-1
PEDF
Associated with insulin

resistance/T2D
Associated with obesity
Plasma IL-6 is positively related to fat

mass [175], elevated in type 2 diabetics
[90, 94]
?
Increased mRNA level in omental
adipose tissue [139] although mice
overexpressing IL-7 have reduced
adipose tissue mass [177]
Higher expression in visceral adipose

tissue in type 2 diabetics and insulin
resistant subjects [91, 178]
Serum MCP-1 is increased in obesity

[129]
PEDF serum levels increased in

obesity [180, 181]
IL-6 promotes insulin resistance

[91, 98, 99]
Associated with improved glucose

metabolism
Insulin-sensitizing effect on skeletal

muscle [102, 104] increases whole
body fat oxidation [109]
n.d.
n.d.
IL-8 plasma levels correlate with

measures of insulin resistance
[97, 179]
n.d.
Promotes insulin resistance [12, 129]
n.d.
PEDF serum levels associated with

insulin resistance [180183], PEDF
promotes insulin resistance [141]
n.d.
: association has been shown in indicated publications; : contradictory data published; n.d.: not described.
Table 3: Concentrations of various factors in conditioned medium from primary human adipocytes and primary human myotubes. Primary
human skeletal muscle cells were differentiated for 5 days and primary human preadipocytes were differentiated for 14 days in vitro to mature
cells. During the last 24 h cells were incubated with serum-free medium to obtain conditioned medium. Concentrations of secreted factors
from cells within this conditioned medium were analyzed by enzyme-linked immunosorbent assay. Data are means SEM, 3.
Secreted factor
Concentration in adipocyte-conditioned
medium (ng/mL)
Concentration in skeletal muscle-conditioned

medium (ng/mL)
2.12 0.3 [141]

2.19 1.4 [11]
0.03 0.002 [141]
0.15 0.04
0.35 0.06
12.64 4.44
45.7 0.82 [141]
0.33 0.09 [141]
0.006 0.001
0.69 0.18
0.02 0.003
0.07 0.01
0.33 0.08
3.44 1.64
5.4 0.86
0.05 0.03
Chemerin
DPP4
IL-6
IL-8
MCP-1
Myostatin
PEDF
VEGF
IL-15 levels and both total and abdominal fat have been
demonstrated [127]. Since both IL-15 and physical exercise
have positive effects on body composition, IL-15 is discussed
as a contraction-regulated myokine in the literature which
may play a role in muscle-fat cross-talk [44, 45] mediating
some of the beneficial effects of physical activity. Yang et al.
published just recently a direct link between treadmill exercise of high-fat diet rats, enhanced expression of IL-15 in
muscle, and increased IL-15 receptor alpha expression in
adipose tissue [52].
17. Other Adipo-Myokines

MCP-1 is one of these adipo-myokines. Before MCP-1 was
characterized as a myokine, it was described to be produced
in isolated adipocytes, associated with adiposity and reduced

after weight loss in morbid obese subjects [128]. It is overexpressed in obese rodents [129, 130] and reaches significantly
higher plasma levels in diabetic patients [131]. In addition,
MCP-1-induced macrophage infiltration in adipose tissue
leads to a chronic state of low-grade inflammation [132],
which is linked to insulin resistance. In vitro data demonstrate
that this factor has the ability to induce insulin resistance in
adipocytes and skeletal muscle cells [12].
Nevertheless, while IL-6, IL-7, IL-8, MCP-1, and pigment
endothelial derived factor (PEDF) are associated with obesity and insulin resistance, these proteins are contractionregulated myokines (Table 1), and only for IL-6 a beneficial
effect has been described (Table 2). The description of a beneficial effect for these myokines is lacking and is an interesting
10
open question for future studies (Table 2). Myostatin is a wellknown myokine, but our group recently identified myostatin
as an adipokine [2].
18. Conclusion
Taken together, one protein can be a myokine as well as an
adipokine, indeed two sides of the same coin. In healthy,
normal weight subjects skeletal muscle is the largest tissue in
the human body, accounting for 4050% of total human body
mass, while body fat accounts for 2035%. In obese subjects
the percentage of total body fat increases to 4060% resulting
in an increased secretion of proinflammatory adipokines,
while the percentage of proteins secreted from skeletal muscle during a sedentary lifestyle is decreased. However, for
many adipo-myokines the local tissue concentration may be
divergent from the serum level, and substantial differences
between auto- and endocrine effects of these molecules need
to be considered.
As Paracelsus (14931541) already coined the famous
phrase; dosis sola facit venenum, Only the dose makes the
poison. This might also be true for adipo-myokines. Findings
support the hypothesis that the myokines are essential for
muscle metabolism during contraction, whereas the chronic
elevation of adipokines released from adipocytes may induce
adverse effects, even leading to insulin resistance.
Abbreviations
AMPK:
ANGPTL4:
BDNF:
DPP4:
FGF:
FNDC5:
FSTL1:
IL:
LIF:
MCP-1:
NT:
PEDF:
TNF:
VEGF:
AMP-activated protein kinase

Angiopoietin like 4
Brain-derived neurotrophic factor
Dipeptidyl peptidase 4
Fibroblast growth factor
Fibronectin type III domain containing
protein 5
Follistatin-like 1
Interleukin
Leukemia inhibitory factor
Monocyte chemoattractant protein 1
Neurotrophins
Pigment endothelial derived factor
Tumor necrosis factor
Vascular endothelial growth factor.
Conflict of Interests
The authors have no conflict of interests in relation to the
contents of this paper.
Acknowledgments
This review article is based on discussions originating from
the PhD thesis of SR. The authors would like to acknowledge
Dr. Kristin Eckardt and Sven W. Gorgens for providing data
on the secretion of myostatin and IL-8 from primary cells
(data shown in Table 3). This work was supported by the
Ministerium fur Wissenschaft und Forschung des Landes
Nordrhein-Westfalen (Ministry of Science and Research of

the State of North Rhine-Westphalia), the Bundesministerium fur Gesundheit (Federal Ministry of Health). This
study was supported in part by a grant from the German
Federal Ministry of Education and Research (BMBF) to the
German Center for Diabetes Research (DZD e.V.)).
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Review Article: Adipo-Myokines: Two Sides of The Same Coin-Mediators of Inflammation and Mediators of Exercise

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1. Skeletal Muscle and Adipose Tissue as

such as skeletal muscle and adipose tissue itself, constituting

Enhanced muscle mRNA

Research of the last decade revealed that several

muscle fibres, skeletal muscle contains extended layers of

3. Secretome of Muscle Cells

4. IL-6: The Best Characterized Myokine

5. IL-15: A Contraction-Regulated Myokine?

6. Irisin: A Novel Myokine

7. BDNF: Released from the Muscle or

9. ANGPTL4: Regulated by Free Fatty Acids

13. IL-6: The Prototype Adipo-Myokine

[2529, 147, 148]

insulin-stimulated glucose disposal in humans and glucose

that the myokine IL-6 is important for muscle metabolism

14. Follistatin Like 1: An Adipo-Myokine

15. Leptin: An Adipokine rather than

In addition, Gorgens et al. recently showed that FSTL1 is

Figure 2: Leptin secretion from primary human myotubes and

accumulation is slightly enhanced in skeletal muscle in obese

16. IL-15: A Myokine rather than

Associated with insulin

Associated with obesity

Plasma IL-6 is positively related to fat

Higher expression in visceral adipose

Serum MCP-1 is increased in obesity

PEDF serum levels increased in

IL-6 promotes insulin resistance

Associated with improved glucose

Insulin-sensitizing effect on skeletal

IL-8 plasma levels correlate with

Promotes insulin resistance [12, 129]

PEDF serum levels associated with

Concentration in skeletal muscle-conditioned

2.12 0.3 [141]

17. Other Adipo-Myokines

in isolated adipocytes, associated with adiposity and reduced

AMP-activated protein kinase

Nordrhein-Westfalen (Ministry of Science and Research of

and exercising human skeletal muscle, PLoS ONE, vol. 7, Article

[63] L. T. Ferris, J. S. Williams, and C. L. Shen, The effect of acute

skeletal muscle of obese type 2 diabetics and elderly subjects,

thermogenesis, Genes & Development, vol. 26, pp. 271281,

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Hindawi Publishing Corporation

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Research and Treatment

Hindawi Publishing Corporation

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Oxidative Medicine and

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