Content uploaded by Michael Scheid
Author content
All content in this area was uploaded by Michael Scheid
Content may be subject to copyright.
The role of adiponectin signaling in metabolic syndrome
and cancer
Michael P. Scheid & Gary Sweeney
#
Springer Science+Business Media New York 2013
Abstract The increased prevalence of obesity has mandated
extensive research focused on mechanisms responsible for
associated clinical complications. Emerging from the focus
on adipose tissue biology as a vitally important adipokine is
adiponectin which is now believed to mediate anti-diabetic,
anti-atherosclerotic, anti-inflammatory, cardioprotective and
cancer modifying actions. Adiponectin mediates these primar-
ily beneficial effects via direct signaling effects and via en-
hancing insulin sensitivity via crosstalk with insulin signaling
pathways. Reduced adiponectin action is detrimental and oc-
curs in obesity via decreased circulating levels of adiponectin
action or development of adiponectin resistance. This review
will focus on cellular mechanisms of adiponectin action, their
crosstalk with insulin signaling a nd the resultant role of
adiponectin in cardiovascular disease, diabetes and cancer
and reviews data from in vitro cell based studies through
animal models to clinical observations.
Keywords Adiponectin
.
Signaling
.
Metabolism
.
Diabetes
.
Cardiovascular disease
.
Cancer
1 Introduction
1.1 Introduction to adiponectin physiology
Due to numerous factors, such as an increase in sedentary
lifestyles combined with poor diet and/or over-nutrition, the
prevalence of overweight and obesity has escalated dramati-
cally and brought with it increases in various associated dis-
ease states [1, 2 ]. For example, it is clear that obesity is
associated with an increased risk for development of type 2
diabetes and var ious forms of cardiovascular disease [2].
Recently, significant emphasis has been placed on associa-
tions between obesity and various forms of cancer and strong
relationships occur [1]. Therefore, the search for mechanisms
responsible for cancer, cardiovascular disease and diabetes in
obesity has become intensive and it is becoming clear that
many answers may lie in the adipose tissue itself. We now
know that as well as fulfilling its traditional role as a site for
storage of excess energy, adipose tissue is an important endo-
crine organ. A large array of adipose-derived factors (collec-
tively termed adipokines) has now been discovered and their
effects characterized [3]. Whereas the majority of adipokines,
such as tumor necrosis factor-α, adipocyte fatty acid binding
protein (A-FABP) and lipocalin-2 are proinflammatory,
adiponectin is one adipokine that has been shown to have
anti-inflammatory, anti-diabetic, cardioprotective and cancer-
altering actions [4–6]. Dysfunctional adipose tissue in obesity
releases a disturbed profile of adipokines with elevated levels
of proinflammatory factors and reduced adiponectin. This
review will focus on adiponectin signaling mechanisms and
the implications of altered adiponectin action in metabolic
syndrome and cancer.
1.2 Crosstalk between adiponectin and insulin signaling
Adiponectin binds to two distinct, seven-transmembrane re-
ceptors (AdipoR1 and AdipoR2) that share 67 % amino acid
identity [7]. AdipoR2 differs significantly with AdipoR1 near
the amino-terminus that resides in the cytoplasm of the cell,
and appears to conduct the majority of the signaling by each
receptor through association with downstream effector mole-
cules. AdipoR1 is expressed ubiquitously and highest in skel-
etal muscle, while AdipoR2 is expressed predominantly in the
liver [7]. The adiponectin receptors communicate to intracel-
lular pathways through the activation of serine/threonine ki-
nases such as AMPK and AKT2, increased phospholipase C
activity, and small G-proteins including Rab5, which will be
M. P. Scheid
:
G. Sweeney (*)
Department of Biology, York University, Toronto,
ON M3J 1P3, Canada
e-mail: gsweeney@yorku.ca
Rev Endocr Metab Disord
DOI 10.1007/s11154-013-9265-5
described in further detail below. Cloning of the adiponectin
receptor [7] and its genetic ablation have accelerated under-
standing of how the adiponectin receptor couples to these
pathways (Fig. 1).
An important function of the adiponectin receptor is to
sensitize and increase the magnitude of insulin signaling on
target cells, facilitating glucose uptake and energy homeostasis
[8]. One way in which adiponectin sensitizes target tissues to
insulin is through the increase in 5′-adenosine monophosphate
kinase (AMPK) activity, whic h stimulates fatty-acid oxidation,
increases PPARa expression, and increases glucose uptake,
while repressing gly colysis, lipid biogenesis and gluconeogen-
esis (reviewed in [9]). In addition, AMPK can directly increase
insulin sensitivity by stimula ting the phosphorylation of perox-
isome proliferator-activated receptor-γ co-activator 1alpha
(PGC-α [10]), a transcription co-activator that plays a crit-
ical role in the biosynthesis of mitochondria and oxidative
phosphorylation. The deacetylase SIR T1 also acts on PGC-α
[11, 12] and both AMPK and SIRT1 appear to act coopera-
tively to fully activate PGC-α [13].
AMPK is a heterotrimeric protein composed of α, β and γ
subunits that stabilize and activate the protein kinase upon
interaction of AMP to Bateman repeats of the γ subunit [14].
An upstream kinase, termed AMPKK, phosphorylates the α
subunit at threonine-172 within the activation loop, which
increases catalytic activity. The primary AMPKK has been
identified as a complex composed of liver kinase B1 (LKB1),
together with two allosteric regulators MO25 and STRAD
[15–17]. CaMKKβ and the transforming growth factor beta-
activated kinase-1 (TAK1) can also serve as AMPKKs under
some conditions [18–21], allowing multiple inputs for activa-
tion depending on the cell type and stimulus. In addition to its
well established role in energy homeostasis, AMPK has also
recently been identified as a tumor suppressor by virtue of its
opposition to aerobic glycolysis [22, 23], and loss of AMPK
or the LKB1-STRAD-MO25 complex accelerates tumorigen-
esis for many human cancers, as will be described below.
Adiponectin can activate AMPK th rough an LKB1-
STRAD-MO25 dependent mechanism, as well as CaMKKβ
mechanism in muscle [24–31]. The mechanism of activation
requires the adapter protein APPL1 [28, 32], which binds to
the N-terminus of the AdipoR1 [28]. APPL1 is composed of a
C-terminal PTB domain, an N-terminal Bin/amphiphysin/Rvs
(BAR) domain, and a central pleckstrin homology (PH) do-
main [32
]. Each domain serves as docking sites for down-
stream effectors, and deletion of each has discrete outcomes;
for example, deletion of the PTB domain disrupts binding to
AdipoR1, while deletion of the BAR domain of APPL1
disrupts binding with LKB1 [28].
Mechanistically, LKB1 is a nucleo-cytoplasmic shuttling
protein [33], and binding to APPL1 could act to shift the
localization of LKB1 to the cytoplasm, thereby increasing
the colocalization of LKB1 with AMPK [31]. An important
question that remains is how adiponectin facilitates APPL1—
LKB1 interaction, and why it is not maintained constitutively
in untreated cells. It is possible that other signals modify either
Fig. 1 Adiponectin sensitizes
Insulin signaling by activating the
metabolic checkpoint kinase
AMPK through APPL1-mediated
recruitment of LKB and
CaMKK2, which increases fatty
acid oxidation through activation
of PPARa. AKT2 associates with
APPL1 and is synergistically
activated by adiponectin and
insulin. AMPK also activates the
GTPase TSC1/TSC2 complex,
which acts on the small G-protein
Rheb. This promotes inactivation
of the mTOR complex 1
(TORC1), suppressing protein
synthesis and shifts the cell away
from aerobic glycolysis. Red
arrows indicate an inhibitor effect
Rev Endocr Metab Disord
APPL1 or LKB1 during adiponectin treatment, which then
directs APPL1—LKB1 association. Zhou and colleagues re-
ported that phospholipase C activity was stimulated by
adiponectin, resulting in intracellular Ca
+2
release [31]. It is
possible that a Ca
+2
activated kinase, such as PKC, could
phosphorylate and alter APPL1. One study did investigate
the potential post-translational modifications of APPL1,
where it was shown to undergo PKCα-mediated phosphory-
lation of Ser430. Use of the phosphorylation prediction pro-
gram Scansite (http://scansite.mit.edu) reveals that APPL1 has
several other potential sites, including Thr177 that lies directly
within the BAR domain and could be targeted by an AGC
kinase such as PKC. Future studies might test whether Thr177
is a phosphorylation site and if this alters LKB1 association. In
addition to APPL1, LKB1 has recently been shown to also
undergo modification following adiponectin stimulation.
Ser307 is required for nuclear localization of LKB1 through
aPKCζ dependent mechanism [34], and phosphorylation of
this site is reduced following adiponectin stimulation [35],
resulting in its cytoplasmic translocation. The mechanism of
dephosphorylation of LKB1 is suggested to be as a result of
reduction in PKCζ activity due to PP2A-mediated dephos-
phorylation [35]. Thus, adiponectin reduces PKCζ activity,
resulting in a shift in the rate of LKB1 nuclear localization.
APPL1 also binds to the protein kinase AKT2 and the cata-
lytic subunit of phosphoinositide-3-kinase (PI3K) [32].
Activation of AKT2 requires co-localization to the plasma mem-
brane, where binding of its PH domain to phosphatidylinositol-
3,4,5-P
3
(PIP
3
) results in a conformation change, relieving auto-
inhibition and allowing accessibility by its upstream kinases
PDK1 and mTOR-containing complex-2 (TORC2; reviewed in
[36]). These kinases phosphorylate AKT2 at Thr309 and Ser474,
respectively, resulting in full activation [37]. PIP
3
is generated by
PI3K, which is activated through binding with phosphotyrosine
sites on the insulin receptor substrate-1 (IRS-1). Since APPL1
binds to AKT2, this could facilitate co-localization with insulin
receptors to amplify the AKT2 driven signal. There is evidence
that this mechanism occurs, as several studies have shown that
adiponectin can synergistically activate AKT2 through an
APPL1-dependent mechanism [28, 38, 39], thereby promoting
glucose uptake and the activation of pro-surv ival pathway in
some cell types, leading to enhanced survival of cells following
stress insu lts. APPL1 als o facilitates Glut4 and insulin receptor
translocation to the plasma membrane through a mechanism that
involves APPL1-dependent activation of the Rab5 G-protein
[28, 40]. In yet another mechanism, APPL1 has been shown to
regulate the interaction between AKT and the AKT inhibitor
protein tribble 3 (TRB3). Overexpression of APPL1 disrupts
AKT-TRB3 interaction, and knockdown of APPL1 augmented
this interaction [41].
In addition to these many associations, APPL1 also binds
with the catalytic domain of PI3K, which may also have
implications on AKT2 activation. Although adiponectin is not
classically thought to stimulate the PI3K pathway, APPL1
could act as a scaffold to facilitate PI3K activation following
tyrosine phosphorylation of IRS1 by the insulin receptor. Since
engagement of the SH2 domains of the p85 subunit of PI3K is
necessary for the activation of PI3KCA, this mechanism would
ensure that adiponecti n could only contribute to AKT2 signal-
ing during periods of insulin stimulation. Consistent with this
model, inhibition o f PI3K with the inhibitors wortmannin or
LY294002 appear to block signaling by the adiponectin recep-
tor [42], suggesting tha t co-localizatio n of PI3K could play an
impo rtant role. Furthermore, expression of AdipoR1 and
AdipoR2 are influenced by PI3K-dependent transcription, in
which AKT phosphorylation of the transcription factor FOXO1
represses ADIPOQR gene activation [43], suggesting a nega-
tive feedback mechanism to limit sensitization.
Finally, adiponectin may also sensitize target cells to insulin
by repressing feedback inhibition signals at the level of the
insulin receptor. For example, growth and anti-apoptotic signals
are induced by tyrosine phosphorylation of IRS1, which binds to
and activates PI3K [44], which in turn activates AKT. This
pathway leads to inactivation of the GTPase complex of TSC1
and TSC2, allowing GTP loading of the small G-protein ras-
homolog enriched in brain (Rheb). Rheb is needed for mTOR
activation within mTOR complex 1 (TORC1), a multiprotein
complex that coordinates mTOR activity, substrate specificity ,
and sensitivity to the macrolide rapamycin [45]. TORC1 phos-
phorylates the p70 S6 ribosomal protein kinase (S6K) within the
hydrophobic motif at Thr389, resulting in full activation, and so
a linear pathway exists that leads from the insulin receptor to
activation of S6K and TORC1. Once activated, TORC1 and
S6K target components of the protein translation machinery and
mitochondrial biogenesis, resulting in cell growth [46].
Following insulin stimulation, IRS1 signaling is negatively
regulated by S6K in a classic feedback inhibition loop [47,
48]. Several groups have shown that adiponectin can promote
increased insulin/IGF-1 signaling by down regulating S6K
activity, which in turn results in the loss of a negative phos-
phorylation event on IRS1, thereby reducing negative feed-
back inhibition [25, 49]. Adiponectin may also increase IRS1
phosphorylation within the YXXM motif at Y612, leading to
binding of the SH2 domain of p85 and activation of PI3K and
AKT [49]. Together these observations are consistent with the
finding that adiponectin can activate the pro-survival PI3K/
AKT pathway in some cell types [38, 39
], leading to survival
of muscle and hepatocytes following stress insults.
1.3 Adiponectin signaling and regulation of metabolism
in cardiovascular disease
Obesity and the associated metabolic syndrome make individ-
uals more inclined to develop cardiovascular dysfunctions
which can be devastating owing to the high risk for mortality
or loss of quality of life [50, 51]. Accordingly, there is strong
Rev Endocr Metab Disord
interest in determining the various ways via which obesity can
influence initiation and progression of cardiovascular disease.
Adiponectin has widespre ad effe cts on cardiovascu lar disease,
and here we will focus on insulin signaling mechanisms regu-
lating direct effects of adiponectin on the heart and also the
vasculature [5, 52].
A large number of studies in adiponectin knockout (Ad-
KO) mice has established that lack of adiponectin exacerbates
stress-induced remodeling events such as hypertrophy, apo-
ptosis and fibrosis and that these can be prevented or corrected
by replenishing adiponectin to these animals [53–58]. Most
importantly, changes in cardiac metabolism are central to the
pathogenesis of heart failure in obesity [2, 59–61]and
adiponectin has been shown to act as an orchestrator of cardiac
fatty acid and glucose uptake and metabol ism. APPL1-
dependent activation of AMPK plays a critical role in medi-
ating cardiometabolic effects of adiponectin [62, 63]. In pri-
mary rat cardiomyocytes adiponectin increased association of
AdipoR1 with APPL1, subsequent binding of APPL1 with
AMPKα2 then phosphorylation and inhibition of ACC [62].
The ensuing increased fatty acid uptake and oxidation could
be attenuated by using siRNA to efficiently knockdown
APPL1 [62]. We have unpublished observations that APPL1
transgenic mice are protected from high fat diet induced
cardiomyopathy. Adiponectin also acts via APPL1 to protect
cardiomyocytes from hypoxia/reoxygenation-induced apo-
ptosis [64]. APPL2 can bind APPL1, sequestering it to pre-
vent the interaction with AdipoR in muscle cells and thus acts
as a negative regulator of adiponectin, and insulin, signaling
[65]. However, little is known yet regarding the role of APPL2
in the heart. In addition to activating AdipoR1-APPL1-
AMPK signaling, adiponectin enhanced insulin-stimulated
Akt phosphorylat ion leading to glucose uptake in primary adult
rat c ardiomyocy tes [62]. Thus, adiponectin enhan ces glucose
uptake via both insulin-mim etic and insulin-sensitizing
mechanisms.
Studies such as those described abov e demonstrating
cardioprotective effects of adipoenctin have been largely sup-
ported by numerous clinical studies which established inverse
correlations between plasma adiponectin levels and occurrence
or severity of heart failure [52]. However, the cardioprotective
role of adiponectin is not without question since various studies
have now found positive correlations between adiponectin
levels and adverse outcome in certain individuals. In particular,
elevated adiponectin levels have been found in late stages of
chronic heart failure and this has been suggested to reflect either
a permissive role of adiponectin or a compensatory increase
designed to overcome the development of adiponectin resis-
tance [66]. The latter is of particular interest and one potential
mechanism of adiponectin resistance is loss of one or more
receptor isoforms. Previous studies have indeed reported that
AdipoR expression was suppressed concomitantly with elevat-
ed adiponectin levels in failing hearts compared with control
subjects, and increased back toward normal levels after me-
chanical unloading [67]. In another study, neither AdipoR1 or
AdipoR2 were found to be altered in hearts from patients with
dilated cardiomyopathy [68]. Cardiac AdipoR1 expression also
decreased early after onse t of streptozotocin-induced diabetes
yet increased after longer duration of diabetes [69] and cardiac
AdipoR2 levels were decreased in diabetic rats [70].
Hyperglycemia or hyperinsulinemia which are common in
many obese individuals can both directly regulate AdipoR
isoform expression [71, 72
]. In addition to correlative studies,
functional tests have shown that a higher dose of adiponectin
was required to blunt oxidative and nitrative stress in hearts of
mice after high fat diet feeding [73]. The well estabilshed effect
of adiponectin to protect against hypoxia reoxygenation in-
duced oxidative stress and cell death was lost using cells
derived from AdipoR1-KO mice [74]. Whether adiponectin
resistance develops and how this occurs must now be more
clearly understood.
Adiponectin signaling in the vasculature also has signifi-
cant impact in vascular function and will be discussed briefly
here. First, adiponectin mediates several effects on the endo-
thelium to combat endothelial dysfunction and the majority of
these depend upon AMPK-mediated signaling. Both
AdipoR1 and AdipoR2 are expressed in endoth elial cells
and adiponectin activates AMPK-dependent phosphorylation
of eNOS to produce nitric oxide and induce vasodilation.
Knockdown of APPL1 expression reduced adiponectin-
stimulated phosphorylation of eNOS at Ser1177, and the
association of eNOS and heat shock protein 90 [75]. These
events resulted in reduced NO production. Adiponectin also
mediates anti-inflammatory effects on endothelium via PKA-
dependent suppression of NF-κB acti vation [76, 77].
Additional beneficial endothelial effects of adiponctin include
attenuating ROS production and decreasing monocyte attach-
ment which, together with inhibition of smooth muscle pro-
liferation and migration contribute to prevention of athero-
sclerosis [5]. A more recent interesting aspect of adiponectin’s
regulation of vascular function is the ability to mobilize and
increase function of endothelial progenitor cells. The phenom-
enon of adiponectin resistance may also pertain to vascular
effects since the expression of APPL1 was reduced in vessels
from various commonly used obese and diabetic animal
models [75, 78, 79].
1.4 Adiponectin signaling and regulation of metabolism
in diabetes
The substantial evidence linking adiponectin to metabolic
syndrome has been extensively reviewed [4, 80]. AdipoR1
and AdipoR2 appear to be the main adiponectin receptor
isoforms involved in mediating the metabolic effects of
adiponectin [80, 81] although there is also evidence that T-
cadherin may mediate or facilitate signaling [82, 83]. In
Rev Endocr Metab Disord
skeletal muscle, adiponectin stimulates glucose uptake via
inducing translocation of the glucose transporter GLUT4 to
the cell surface [84] and this effect was abolished upon knock-
down of APPL1 using siRNA [28]. An important downstream
target of AdipoR/APPL1 signaling in mediating metabolic
effects is AMPK [80, 81]. Adiponectin also enhances insulin
sensitivity and dominant negative AMPK overexpression in
muscle reduced the insulin sensitizing action of adiponectin
[25, 85]. AdipoR-APPL1-AMPK signaling has also been
shown to be important in mediating hepatic metabolic effects
of adiponectin [86].
Various mouse models have been informative in determin-
ing the metabolic consequences of ad iponec tin signaling
patways. First, adiponectin knockout mice have a relatively
normal phenotype until challenged by a stress such as high fat
diet, under which conditions they tend to show exacerbated
insulin reistance and metabolic dysfunction [87–89]. Deletion
of both AdipoR1 and R2 in mice led to increased lipid accu-
mulation in various tissues, insulin resistance and glucose
intolerance [ 90]. AdipoR1 deletion results in lack of
adiponectin-stimulated AMPK activation and upon AdipoR2
deletion the principal signaing defect occurs in PPARα sig-
naling [90]. AdipoR1 KO mice exhbited decreased glucose
tolerance and defects in AMPK activation [90, 91]whereas
young AdipoR2 KO mice were found to have improved
glucose tolerance and lipid profiles in response to high fat diet
yet older mice had worse metabolic dysfunction [91]. Deletion
of AdipoR1 specifically in skeletal muscle led to defects in
peripheral glucose homeostasis [24]. Introduction of APPL1
to skeletal muscle in rats by electrotransfer-mediated
overexpression enhanced insulin-stimulated glucose disposal
[92]. Recently, mice lacking the APPL1 gene were generated
and phenotypically normal, and isolated embryonic fibro-
blasts stimulated with insulin showed no change in activation
of AKT1 or AKT2 [93]. Whether these results are a result of
compensatory effects involving APPL2 or some other protein
as a result of chronic depletion of APPL1 are not clear.
Adiponectin enhanced skeletal muscle biogenesis and a fiber
type switch to provide more oxidative capacity through an
AMPK-myocyte enhancer factor 2C (MEF2C)-PGC1α path-
way [24, 94, 95].
Adiponectin resistance is also likely to be a physiologically
relevant phenomenon in peripheral metabolic tissues and in-
deed insulin may be one important regulator of peripheral
adiponectin sensitivity. Providing insulin to streptozotocin-
induced diabetic mice reduced the elevated levels of AdipoR
expression found in liver and skeletal muscle of these animals
[43]. Insulin treatment of L6 skeletal muscle cells decreased
AdipoR1 levels while contrasting effects have been reported
on AdipoR2 [43, 72]. In L6 cells high glucose treatment also
reduced AdipoR1 and AdipoR2 expression in L6 cells [72].
Exercise can influence AdipoR expression in various tissues
[96] and more recent studies have shown increased expression
of APPL1 in response to exercise [
97, 98]. APPL1 ex-
pression and phosphorylation on Ser401 were elevated in obese
individuals with type 2 diabetes and reduced after bariatric
surge ry [99].
1.5 Adiponectin signaling and regulation of metabolism
in cancer
In addition to metabolic disease, the importance of nutrient
and energy homeostasis is becoming increasingly evident for
other pathologies such as cancer, where a fine balance is
achieved to optimize cell division, evade apoptosis, and es-
cape the localized stromal environment to metastasize to
distant organs [100, 101]. Furthermore, cancer is a multifac-
torial disease characterized by transformation-dependent ge-
nomic lesions, which act in cooperation with both the system-
ic environment and the tumor microenvironment. Importantly,
circulating and localized hormones and other soluble regula-
tors produced by adipose tissue can both positively and neg-
atively alter tumor growth. These effects could include alter-
ations of tumor physiology, immune system activation, pro-
moting angiogenesis, and by influencing metastasis to distant
organs [102]. Since caloric intake and obesity are associated
with cancer risk [6, 103–105], it is likely that circulating
hormones produced by adipocytes, such as adiponectin, play
a significant role in malignancies [6]. In particular, breast
cancer is uniquely positioned t o interact with adipose-
derived factors since breast tissue is predominantly adipose
tissue, providing an adipocytokine microenvironment that
interacts with the evolving tumor mass.
In the context of cancer initiation and acceleration, obesity
and insulin resistance correlates positively with tumor growth
and poor prognosis. Under these same conditions, circulating
adiponectin levels are low, suggesting that adiponectin could
therefore have anti-cancer actions [106, 107]. Direct correlations
between adiponectin levels and breast cancer incidence have
been recorded by numerous studies, with all demonstrating a
moderate to strong association between lower serum adiponectin
levels and breast cancer risk [108–112]. Furthermore, several
in vitro studies have examined cultured breast cancer cell lines
and their response to exogenously added adiponectin [27,
113–121], and there appears to be a consistent repressive effect
on growth, adhesion and migration caused by adiponectin. A
limitation of these studies, however, is the use of transformed,
aneuploidic cell lines in all cases. In addition, the interac tion
between tumor cell and the stroma is absent and therefore other
signaling factors that could crosstalk and alter the genetic profile
of adiponectin-induced gene expression are lost. Finally , serum
levels of adiponectin may not represent the localized microenvi-
ronment of the breast tumor or the predominant adipocyte-
derived stroma, confounding observations made solely on circu-
lating concentrations.
Rev Endocr Metab Disord
One genetic study performed with mice showed that re-
duced expression of adiponectin could lead to accelerated
breast cancer initiation [12 2]. These authors’ utilized
MMTV-driven polyomavirus middle T antigen transgenic
mice within an adiponectin haplodeficient background.
Tumors grew faster, were more aggressive, and displayed
increased activation of PI3K/AKT. Inactivation of PTEN in
these tumors was noted and occurred as a result of thioredoxin
conjugation, suggesting that reduced adiponectin promotes
tumorigenesis by promoting thioredoxin adducts [122]. It
remains to be determined if this is a general mechanism that
also occurs in human breast tumors.
1.6 Adiponectin inhibition of the Warburg effect
It has been known for years that tumor cells become
“addicted” to aerobic glycolysis as a primary source of energy
and biosynthetic materials, in a process termed the Warburg
effect for its first observation by Otto Warburg more than
80 years ago (reviewed in [100, 123]). In this process, tumor
cells become less reliant on oxidative phosphorylation by
mitochondria and instead rely on conversion of pyruvate to
lactate by lactate dehydrogenase A and inactivation of pyru-
vate dehydrogenase, yielding just two molecules of ATP per
molecule of glucose [101, 123]. The heavy dependence on
aerobic glycolysis as the sole source of energy is thought to
arise as a survival mechanism during anaerobic conditions
within the hypoxic tumor; however, even in the presence of
oxygen tumor cells still turn to aerobic glycolysis. A theory
behind the preference is to maximize proliferation while also
providing the building blocks for the anabolic synthesis of
biomass in the form of nucleic acids, lipids and amino acids
[100, 101].
At a critical point in the decision towards aerobic glycolysis
is AMPK [22, 23]. Normally, AMPK is activated during
periods of low nutrient availability and inhibits TORC1 by
promoting the activity of the GTPase complex TSC1/TSC2,
effectively the opposite result of AKT activation and its inhib-
itory phosphorylation of TSC1/TSC2. This ensures that pro-
tein synthesis is reduced when insufficient nutrients are pres-
ent, and shunts the cell towards optimized ATP production via
oxidative phosphorylation and catabolic metabolism [23].
Low TORC1 signaling is not the condition that a tumor cell
prefers and, not surprisingly, the AMPK axis therefore func-
tions as a linear tumor suppressor pathway, by restricting
TORC1 signaling. For example, LKB1 is deleted or mutated
in sporadic cancer and is mutated in the familial Peutz-Jeghers
syndrome [124, 125]. Likewise, TSC1 and TSC2 are also
tumor suppressors and are mutated in the harmatoma syn-
drome Tuberous Sclerosis Complex [126]. Loss of phospha-
tase with pleckstrin homology on chromosome 10 (PTEN), a
genetic event that occurs in the majority of human cancers,
ameliorates the suppression of TORC1 by AMPK. Thus,
AMPK-activation of nutrient-dependent checkpoints is over-
come in some cancers as a means to bypass growth inhibition.
Importantly, induced activation of AMPK [22, 127]orre-
expression of LKB1 [128] in tumor cells reduces aerobic
glycolysis and slows tumor growth, indicating that AMPK
directly impacts on the decision to revert to glycolysis.
Mechanistically, repression of cell growth by adiponectin
could then involve a divergence of a tumor cell away from
glycolysis, thereby acting to slow cell growth and regulate
energy homeostasis under these conditions by repressing ini-
tiation of protein translation, elevating glucose uptake and
increasing fatty-acid oxidation [7, 24, 30, 129].
Future work will be needed to establish genetic models that
precisely activate or disrupt adiponectin/APPL1/AMPK sig-
naling in the context of tumor evolution that relies on aerobic
glycolysis. While the knockout of APPL1 has resulted in a
surprisingly mild phenotype under normal conditions [93], it
would be interesting to use this genetic background and others
such as AdipoR1/2 knockout to evaluate breast tumor growth
and metastasis where the long term down-regulation of
adiponectin signaling could be evaluated.
1.7 Adiponectin and a potential positive effect on breast
cancer
Although current evidence suggests that adiponectin sup-
presses tumor initiation and progression, there are some inter-
esting observations that might suggest t hat adiponectin c ould
also play a positive role. Takahata and colleagues reported that
Adiponectin
20 - 2 ug/ml
Direct
signaling
effects
Crosstalk
with insulin
signaling
Beneficial metabolic effects
Healthy individual
Defective adiponectin action
Metabolic dysfunction
Diabetes
CVD
Cancer
Reduced circulating or
local adiponectin levels
Adiponectin resistance
Fig. 2 Adiponectin action is altered in normal weight and obese individ-
uals. First, positive direct and insulin-sensitizing actions of adiponectin
are lost in obesity. One reason is that the normally high circulating
adiponectin concentration is reduced in obesity. Obesity may also induce
defective adiponectin action (adiponectin resistance) leading to metabolic
dysfunction. Ensuing disease states can include cardiovascular disease
(CVD), diabetes and cancer
Rev Endocr Metab Disord
AdipoR1 is present on breast cancer cell lines (MCF7, T47D,
MDA-MD231) and breast canc er tissue biopsies [130] breast
cancer tumors, and Karaduman studied 27 breast cancer pa-
tients and found that the localized concentrations of adiponectin
in breast tissue was elevated significantly compared to control
subjects [131]. Thus, compared with an overall trend towards
lower adiponectin serum levels in cancer patients, the localized
microenvironment could present a very different picture.
Specifically, we hypothesize that tumors, if they have ge-
netically inactivated the LKB1-AMPK axis, could benefit
from adiponectin stimulation by synergistically stimulating
insulin-and IGF1-induced signals; for example they could
experience increased PI3K/AKT activation and increased
Glut4 translocation and glucose uptake, and increased
recycling of insulin receptors to the plasma membrane via
Rab5. We performed meta-analysis of The Cancer Genome
Atlas (TCGA) that showed that AdipoR1 mRNA was
upregulated in 22 % of luminal A/B tumors (70 of 324).
Importantly, there was a significant reduction in survival time
in cases with upregulated AdipoR1 (P=0.004; Fig. 2). Clearly,
AdipoR1 protein expression, effects on downstream effectors,
and analysis of other genomic alterations are needed to under-
stand this preliminary observation. However, it does suggest
that adiponectin could play a role in the acceleration of some
types of luminal breast cancers, and argues that further inves-
tigation of this pathway is warranted.
In summary, it is clear from the above information that
correlations exist between adiponectin expression or changes
in adiponectin action and diseases such as cancer, cardiovas-
cular disease and diabetes. In particular, the adiponectin sig-
naling axis of AdipoR1 or AdipoR2, APPL1 and AMPK
appear to play a central role in many important actions of
adiponectin. Although current drugs can act at least in part via
enhancing adiponectin action, for example thiazolidinediones,
it is to be hoped that our current detailed understanding of
adiponectin signaling can be harnassed to develop new ther-
apeutics which can combat the clinical outcomes of disturbed
adiponectin function.
Acknowledgements Related work in the authors laboratories has been
supported by Canadian Institutes of Health Research, Canadian Diabetes
Association and Heart & Stroke Foundation of Canada. GS acknowl-
edges a Career Investigator Award from Heart & Stroke Foundation of
Ontario. We thank Hana Kim for graphic design assistance in Fig. 2.
Conflict of interest The authors declare that there is no conflict of
interest pertaining to the content of this review article.
References
1. Vucenik I, Stains JP. Obesity and cancer risk: Evidence, mecha-
nisms, and recommendations. [ Review]. Ann N Y Acad Sci.
2012;1271:37–43. doi:10.1111/j.1749-6632.2012.06750.x.
2. Despres JP. Body fat distribution and risk of cardiovascular disease: An
update. [Research suppo rt, Non-U.S. Gov’t Revie w]. Circulation.
2012;126(10):1301–13. doi:10.1161/CIRCULATIONAHA.111.
067264.
3. Harwood Jr HJ. The adipocyte as an endocrine organ in the regu-
lation of metabolic homeostasis. Neuropharmacology.
2012;63(1):57–75. doi:10.1016/j.neuropharm.2011.12.010.
4. Dadson K, Liu Y, Sweeney G. Adiponectin action: A combination
of endocrine and autocrine/paracrine effects. Front Endoc rinol
(Lausanne). 2011;2:62. doi:10.3389/fendo.2011.00062.
5. Hui X, Lam KS, Vanhoutte PM, Xu A. Adiponectin and cardiovas-
cular health: An update. Br J Pharmacol. 2012;165(3):574–90.
doi:10.1111/j.1476-5381.2011.01395.x.
6. Dalamaga M, Diakopoul os K N, M antzoros CS. The role of
adiponectin in cancer: A review of current evidence. Endocr Rev.
2012;33(4):547–94. doi:10.1210/er.2011-1015.
7. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al.
Cloning of adiponectin receptors that mediate Antidiabetic meta-
bolic effects. [Research support, Non-U.S. Gov’t]. Nature.
2003;423(6941):762–9. doi:10.1038/nature01705.
8. Hall J, Roberts R, Vora N. Energy homoeostasis: The roles of adipose
tissue-derived hormones, peptide YY and Ghrelin. Obesity Facts.
2009;2(2):117–25.
9. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors.
Endocr Rev. 2005;26(3):439–51. doi:10.1210/er.2005-0005.
10. Jäger S, Handschin C, St.-Pierre J, Spiegelman BM. AMP-activated
protein kinase (AMPK) action in skeletal muscle via direct phos-
phorylation of PGC-1alpha. Proc Natl Acad Sci.
2007;104(29):12017–22. doi:10.1073/pnas.0705070104.
11. Nemoto S, Fer gusson MM, Finkel T. SIRT1 Functionally interacts
with the metabolic regulator and transcriptional coactivator PGC-
1Œ±. J Biol Chem. 2005;280(16):16456–60. doi:10.1074/jbc.
M501485200.
12. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver
P. Nutrient control of glucose homeostasis through a complex of
PGC-1alpha and SIRT1. Nature. 2005;434(7029):113–8. doi:10.
1038/nature03354.
13. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne
JC, et al. AMPK regulates ene rgy expenditure by modulating
NAD+metabolism and SIRT1 activity. Nature. 2009;458(7241):
1056–60. doi:10.1038/nature07813.
14. Hardie DG, Alessi DR. LKB1 And AMPK and the cancer-metabolism
link—ten years after . BMC Biol. 2013;1 1:36. doi:10.1186 /1741-7007-
11-36.
15. Zeqiraj E, Fi lippi BM, Deak M, Alessi DR, van Aalten DM.
Structure of the LKB1-STRAD-MO25 complex reveals an alloste-
ric me chanism of kinase activation. Sc ience. 2009;326(5960):
1707–11. doi:10.1126/science.1178377.
16. Boudeau J, Baas AF, Deak M, Morrice NA, Kieloch A,
Schutkowski M, et al. MO25alpha/beta interact with
STRADalpha/beta enhancing their ability to bind, activate and
localize LKB1 in the cytoplasm. EMBO J. 2003;22(19):5102–14.
doi:10.1093/emboj/cdg490.
17. Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA,
et al. Activation of the tumour suppressor kinase LKB1 by the
STE20-like pseudokinase STRAD. EMBO J. 2003;22(12):3062–
72. doi:10.1093/emboj/cdg292.
18. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M,
Johnstone SR, et al. Ca2+/calmodulin-dependent protein kinase
kinase-beta acts upstream of AMP-activated protein kinase in mam-
malian cells. Cell Metab. 2005;2(1):21–33. doi:10.1016/j.cmet.2005.
06.005.
19. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM,
et al. Calmodulin-dependent protein kinase kinase-beta is an alter-
native upstream kinase for AMP-activated protein kinase. Cell
Metab. 2005;2(1):9–19. doi:10.1016/j.cmet.2005.05.009.
Rev Endocr Metab Disord
20. Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C,
Farkas T, Lopez-Rivas A, et al. TAK1 activates AMPK-dependent
cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO
J. 2009;28(6):677–85. doi:10.1038/emboj.2009.8.
21. Momcilovic M, Hong SP, Carlson M. Mammalian TAK1 activates
Snf1 protein kinase in yeast and phosphorylates AMP-activated
protein kinase in vitro. J Biol Chem. 2006;281(35):25336–43.
doi:10.1074/jbc.M604399200.
22. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al.
AMPK is a negative regulator of the Warburg effect and suppresses
tumor growth in vivo. Cell Metab. 2013;17(1):113–24.
23. Dandapan i M , Hardie DG. AMPK : Oppo sing t he m etabolic
changes in both tumour cells and inflammatory cells? Biochem
Soc Trans. 2013;41(2):687–93. doi:10.1042/bst20120351.
24. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T,
Funata M, et al. A diponectin and AdipoR1 regulate PGC- 1alpha
and mitochondria by Ca(2+) and AMPK/SIR T1. [Research support,
Non-U.S. Gov’t]. Nature. 2010;464(7293):1313–9. doi:10.1038/
nature08991.
25. Wang C, Mao X, Wang L, Liu M, Wetzel MD, Guan KL, et al.
Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-
mediated serine phosphorylation of IRS-1. [Research Support,
N.I.H., Extramural Research Support, Non-U.S. Gov’t]. The
Journal of biological chemistry. 2007;282(11):7991–6. doi:10.
1074/jbc.M700098200.
26. Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD, et al.
Dietary energy balance modulates signaling through the Akt/
mammalian target of rapamycin pathways in multiple epithelial
tissues. Cancer prevention research. 2008;1(1):65–76. doi:10.
1158/1940-6207.capr-08-0022.
27. Taliaferro-Smith L, Nagalingam A, Zhong D, Zhou W, Saxena NK,
Sharma D. LKB1 is required for adiponectin-mediated modulation
of AMPK-S6K axis and inhibition of migration and invasion of
breast cancer cells. Oncogene. 2009;28(29):2621–33. doi:10.1038/
onc.2009.129.
28. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ,
et a l. AP PL1 binds to adiponectin receptors and mediates
adiponectin signaling and function. [Research Support, N.I.H.,
Extramural Research Support, Non-U.S. Gov’t]. Nature cell biolo-
gy . 2006;8(5):516–23. doi:10.1038/ncb1404.
29. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H,
et al. Adiponectin stimulates AMP-activated protein kinase in the
hypothalamus and increases food intake. Cell Metab. 2007;6(1):55–
68. doi:10.1016/j.cmet.2007.06.003.
30. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al.
Adiponectin stimulates glucose utilization and fatty-acid oxidation
by activating AMP-activated protein kinase. Nature medicine.
2002;8(11):1288–95. doi:10.1038/nm788.
31. Zhou L, Deepa SS, Etzler JC, Ryu J, Mao X, Fang Q, et al.
Adiponectin activates AMP-activated protein kinase in muscle cells
via APPL1/LKB1-dependent and Phospholipase C/Ca2+/Ca2+/cal-
modulin-dependent protein kinase kinase-dependent pathways. J Biol
Chem. 2009;284(33):22426
–35 . doi:10.1074/jbc.M109 .028357.
32. Mitsuuchi Y, Johnson SW, Sonoda G, T anno S, Golemis EA, Testa
JR. Identification of a chromosome 3p14.3-21.1 gene, APPL,
encoding an adaptor molecule that interacts with the oncoprotein-
serine/threonine kinase AKT2. Oncogene. 1999;18(35):4891–8.
doi:10.1038/sj.onc.1203080.
33. Boudeau J, Scott JW, Resta N, Deak M, Kieloch A, Komander D,
et al. Analysis of the LKB1-STRAD-MO25 complex. J Cell Sci.
2004;117(Pt 26):6365–75. doi:10.1242/jcs.01571.
34. Xie Z, Dong Y, Zhang J, Scholz R, Neumann D, Zou MH.
Identification of the serine 307 of LKB1 as a novel phosphorylation
site essential for its nucleocytoplasmic transport and endothelial cell
angiogenesis. Mol Cell Biol. 2009;29(13):3582–96. doi:10.1 128/mcb.
01417-08.
35. Deepa SS, Zhou L, Ryu J, Wang C, Mao X, Li C, et al. APPL1
Mediates adiponectin-induced LKB1 cytosolic localization through
the PP2A-PKCζ signaling pathway. Mol Endocrinol. 2011;25
(10):1773–85. doi:10.1210/me.2011-0082.
36. Manning BD, Cantley LC. AKT/PKB signaling: Navigating down-
stream. Cell. 2007;129(7):1261–74. doi:10.1016/j.cell.200 7.06.
009.
37. Scheid MP, Woodgett JR. Unravelling the activation mechanisms of
protein kinase B/Akt. FEBS Lett. 2003;546(1):108–12.
38. Patel SA, Hoehn KL, Lawrence RT, Sawbridge L, Talbot NA,
Tomsig JL, et al. Overexpression of the adiponectin receptor
AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity.
Endocrinology. 2012;153(11):5231– 4 6. doi:10.1210/en.2012-
1368.
39. Maruyama S, Shibata R, Ohashi K, Ohashi T, Daida H, Walsh K,
et al. Adiponectin ameliorates doxorubicin-induced cardiotoxicity
through Akt protein-dependent mechanism. [Research Support,
Non-U.S. Gov’t]. The Journal of biological chemistry.
2011;286(37):32790–800. doi:10.1074/jbc.M1 11.245985.
40. Saito T, Jones CC, Huang S, Czech MP, Pilch PF. The interaction of
Akt with APPL1 is required for insulin-stimulated Glut4 transloca-
tion. J Biol Chem. 2007;282(44):322 80– 7 . doi:10.1074/jbc.
M704150200.
41. Cheng KKY, Iglesias MA, Lam KSL, Wang Y, Sweeney G, Zhu W,
et al. APPL1 Potentiates Insulin-Mediated Inhibition of Hepatic
Glucose Production and Alleviates Diabetes via Akt Activation in
Mice. Cell Metab. 2009;9(5):417–27.
42. Wijesekara N, Krishnamurthy M, Bhattacharjee A, Suhail A,
Sweeney G, Wheeler MB. Adiponectin-induced ERK and Akt
phosphorylation protects against pancreatic beta cell apoptosis and
increases insulin gen e expression and secretion. J Biol Chem.
2010;285(44):33623–31. doi:10.1074/jbc.M109.085084.
43. Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, Takekawa S, et al.
Insulin/Foxo1 pathway regulates expression levels of adiponectin
receptors and adiponectin sensitivity. J Biol Chem.
2004;279(29):30817–22. doi:10.1074/jbc.M402367200.
44. Backer JM, Myers Jr MG, Shoelson SE, Chin DJ, Sun XJ, Miralpeix
M, et al. Phosphatidylinositol 3′
-kinase is activated by association with
IRS-1 during insulin stimulation. EMBO J. 1992;11(9):3469–79.
45. Cornu M, Albert V, Hall MN. mTOR in aging, metabolism, and
cancer. Curr Opin Genet Dev. 2013;23(1):53–62. doi:10.1016/j.gde.
2012.12.005.
46. Magnuson B, Ekim B, Fingar DC. Regulation and function of
ribosomal protein S6 kinase (S6K) within mTOR signaling net-
works. Biochem J. 2012;441(1):1–21. doi:10.1042/bj20110892.
47. Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE. Insulin
resistance Due to phosphorylation of insulin receptor substrate-
1 at serine 302. J Biol Chem. 2004;279(34):35298–305. doi:10.
1074/jbc.M405203200.
48. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S,
Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin
–PI3K signaling via regulation of IRS proteins. The Journal of
Cell Biology. 2004;166(2):213–23. doi:10.1083/jcb.200403069.
49. Vu V, Kim W, Fang X, Liu YT, Xu A, Sweeney G. Coculture with
primary visceral rat adipocytes from control but not Streptozotocin-
induced diabetic animals increases glucose uptake in rat skeletal
muscle cells: Role of adiponectin. [Research support, Non-U.S.
Gov’t]. Endocrin ology. 2007;148(9):441 1–9. doi:10.1210/en.2007-
0020.
50. Gaddam KK, Ventura HO, Lavie CJ. Metabolic syndrome and heart
failure–the risk, paradox, and treatment. [Review]. Curr Hypertens
Rep. 2011;13(2):142–8. doi:10.1007/s11906-011-0179-x.
51. Anker SD, von Haehling S. The obesity paradox in heart failure:
Accepting reality and making rational decisions. [Research support,
Non-U.S. Gov’t Review]. Clin Pharmacol Ther. 2011;90(1):188–
90. doi:10.1038/clpt.2011.72.
Rev Endocr Metab Disord
52. Park M, Sweeney G. Direct effects of adipokines on the heart: Focus on
adiponectin. Heart Fail Rev . 2013. doi:10.1007/s10741-012-9337-8.
53. Fujita K, Maeda N, Sonoda M, Ohashi K, Hibuse T, Nishizawa H,
et al. Adiponectin protects against angiotensin II-induced cardiac
fibrosis through activation of PPAR-alpha. Arterioscler Thromb
Vasc Biol. 2008;28(5):863–70.
54. Shibata R, Sato K, Pimentel DR, Takemura Y, Kihara S, Ohashi K,
et al. Adiponectin protects against myocardial ischemia-reperfusion
injury through AMPK- and COX-2-dependent mechanisms. Nat
Med. 2005;11(10):1096–103.
55. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, et al.
Adiponectin-mediated modulation of hypertrophic signals in the
heart. Nat Med. 2004;10(12):1384–9.
56. Shibata R, Izumiya Y, Sato K, Papanicolaou K, Kihara S, Colucci WS,
et al. Adiponectin protects against the development of systolic dysfunc-
tion following myocardial infarction. J Mol Cell Cardiol.
2007;42(6):1065–74.
57. Sam F, Duhaney TA, Sato K, Wilson RM, Ohashi K, Sono-
Romanelli S, et al. Adiponectin deficiency, diastolic dysfunction,
and diastolic heart failure. [Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov’t]. Endocrinology. 2010;151(1):
322–31. doi:10.1210/en.2009-0806.
58. Shimano M, Ouchi N, Shibata R, Ohashi K, Pimentel DR,
Murohara T, et al. Adiponectin deficiency exacerbates cardiac
dysfunction following pressure overload through disruption of an
AMPK-dependent angiogenic response. [Research Support, N.I.H.,
Extramural Research Support, Non-U.S. Gov’t]. J Mol Cell
Cardiol. 2010;49(2):210–20. doi:10.1016/j.yjmcc.2010.02.021.
59. Leroith D. Pathophysiology of the metabolic syndrome: implica-
tions for the cardiometabolic risks associated with type 2 diabetes.
[Review]. Am J Med Sci. 2012;343(1):13–6. doi:10.1097/MAJ.
0b013e31823ea214.
60. Abel ED, Litwin SE, Sweeney G. Cardiac remodeling in obesity.
Physiol Rev. 2008;88(2):389–419.
61. Despres JP, Cartier A, Cote M, Arsenault BJ. The concept of
cardiometabolic risk: Bridging the fields of diabetology and cardi-
ology. [Research Support, Non-U.S. Gov’t Review]. Ann Med.
2008;40(7):514–23. doi:10.1080/07853890802004959.
62. Fang X, Palanivel R, Cresser J, Schram K, Ganguly R, Thong FS,
et al. An APPL1-AMPK signaling axis mediates beneficial meta-
bolic effects of adiponectin in the heart. [In Vitro Research Support,
N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Am J
Physiol Endocrinol Metab. 2010;299(5):E721–729. doi:10.1152/
ajpendo.00086.2010.
63. Palanivel R, Fang X, Park M, Eguchi M, Pallan S, De Girolamo S,
et al. Globular and full-length forms of adiponectin mediate specific
changes in glucose and fatty acid uptake and metabolism in
cardiomyocytes. Cardiovasc Res. 2007;75(1):148–57.
64.ParkM,YounB,ZhengXL,WuD,XuA,SweeneyG.Globular
adiponectin, acting via AdipoR1/APPL1, protects H9c2 cells from
hypoxia/reoxygenation-induced apoptosis. [Research Support, Non-
U.S. Gov’t]. PLoS One. 2011;6(4):e19143. doi:10.1371/journal.pone.
0019143.
65. Wang C, Xin X, Xiang R, Ramos FJ, Liu M, Lee HJ, et al. Yin-Yang
regulation of adiponectin signaling by APPL isoforms in muscle
cells. J Biol Chem. 2009;284 (46):31608–15. doi:10.1074/jbc.
M109.010355.
66. Ebert T, Fasshauer M. Adiponectin: Sometimes good, sometimes
bad? Cardiology. 2011;118(4):236–7. doi:10.1159/000329647.
67. Khan RS, Kato TS, Chokshi A, Chew M, Yu S, Wu C, et al.
Adipose tissue inflammation and adiponectin resistance in patients
with advanced heart failure: Correction after ventricular assist de-
vice implantation. Circ Heart Fail. 2012;5(3):340–8. doi:10.1161/
CIRCHEARTFAILURE.111.964031.
68. Skurk C, Wittchen F, Suckau L, Witt H, Noutsias M, Fechner H,
et al. Description of a local cardiac adiponectin system and its
deregulation in dilated cardiomyopathy. [Research Support, Non-
U.S. Gov’t]. Eur Heart J. 2008;29(9):1168–80 . doi:10.1093/eurheartj/
ehn136.
69. Ma Y, Liu Y, Liu S, Qu Y, W ang R, Xia C, et al. Dynamic alteration of
adiponectin/adiponectin receptor expression and its impact on myocar-
dial ischemia/reperfusion in type 1 diabetic mice. Am J Physiol
Endocrinol Metab. 2011;301(3):E447–455. doi:10.1152/ajpendo.
00687.2010.
70. Wang T, Qiao S, Lei S, Liu Y, Ng KF, Xu A, et al. N-acetylcysteine
and allopurinol synergistically enhance cardiac adiponectin content
and reduce myocardial reperfusion injury in diabetic rats. PLoS
One. 2011;6(8):e23967. doi:10.1371/journal.pone.0023967.
71. Cui XB, Wang C, Li L, Fan D, Zhou Y, Wu D, et al. Insulin
decreases myocardial adiponectin receptor 1 expression via PI3K/
Akt and FoxO1 pathway. [Research Support, Non-U.S. Gov’t].
Cardiovasc Res. 2012;93(1):69–78. doi:10.1093/cvr/cvr273.
72. Fang X, Palanivel R, Zhou X, Liu Y, Xu A, Wang Y, et al.
Hyperglycemia-and hyperinsulinemia-induced alteration of
adiponectin receptor expression and adiponectin effects in L6 myo-
blasts. [Research Support, Non-U.S. Gov’t]. J Mol Endocrinol.
2005;35(3):465–76. doi:10.1677/jme.1.01877.
73. Yi W, Sun Y, Gao E, Wei X, Lau WB, Zheng Q, et al. Reduced
cardioprotective action of adiponectin in high-fat diet-induced type
II diabetic mice and its underlying mechanisms. [Research Support,
N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Antioxid
Redox Signal. 2011;15(7):1779–88. doi:10.1089/ars.2010.3722.
74. Wang C, Li L, Zhang ZG, Fan D, Zhu Y, Wu LL. Globular
adiponectin inhibits angiotensin II-induced nuclear factor kappaB
activation through AMP-activated protein kinase in cardiac hyper-
trophy. [Research Support, Non-U.S. Gov’t]. J Cell Physiol.
2010;222(1):149–55. doi:10.1002/jcp.21931.
75. Cheng KK, Lam KS, Wang Y, Huang Y, Carling D, Wu D, et al.
Adiponectin-induced endothelial nitric oxide synthase activation
and nitric oxide production are mediated by APPL1 in endothelial
cells. Diabetes. 2007;56(5):1387–94. doi:10.2337/db06-1580.
76. Wu X, Mahadev K, Fuchsel L, Ouedraogo R, Xu SQ, Goldstein BJ.
Adiponectin suppresses IkappaB kinase activation induced by tu-
mor necrosis factor-alpha or high glucose in endothelial cells: role of
cAMP and AMP kinase signaling. Am J Physiol Endocrinol Metab.
2007;293(6):E1836–1844. doi:10.1152/ajpendo.00115.2007.
77. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H,
et al. Adiponectin, an adipocyte-derived plasma protein, inhibits
endothelial NF-kappaB signaling through a cAMP-dependent path-
way. Circulation. 2000;102(11):1296–301.
78. Wang Y, Cheng KK, Lam KS, Wu D, Huang Y, Vanhoutte PM, et al.
APPL1 counteracts obesity-induced vascular insulin resistance and
endothelial dysfunction by modulating the endothelial production of
nitric oxide and endothelin-1 in mice. Diabetes. 2011;60(11):3044–
54. doi:10.2337/db11-0666.
79. Schmid PM, Resch M, Steege A, Fredersdorf-Hahn S, Stoelcker B,
Birner C, et al. Globular and full-length adiponectin induce NO-
dependent vasodilation in resistance arteries of Zucker lean but not
Zucker diabetic fatty rats. Am J Hypertens. 2011;24(3):270–7.
doi:10.1038/ajh.2010.239.
80. Turer AT, Scherer PE. Adiponectin: Mechanistic insights and clin-
ical implications. Diabetologia. 2012;55(9):2319–26. doi:10.1007/
s00125-012-2598-x.
81. Yamauchi T, Kadowaki T. Adiponectin receptor as a key player in
healthy longevity and obesity-related diseases. Cell Metab.
2013;17(2):185–96. doi:10.1016/j.cmet.2013.01.001.
82. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao TS, Lodish HF. T-
cadherin is a receptor for hexameric and high-molecular-weight
forms of Acrp30/adiponectin. Proc Natl Acad Sci U S A.
2004;101(28):10308–13. doi:10.1073/pnas.0403382101.
83. Ordelheide, A. M., Heni, M., Gommer, N., Gasse, L., Haas, C.,
Guirguis, A., et al. The myocyte expression of adiponectin receptors
Rev Endocr Metab Disord
and PPARdelta is highly coordinated and reflects lipid metabolism
of the human donors. [Research Support, Non-U.S. Gov’t]. Exp
Diabetes Res, 2011, 692536, doi:10.1155/2011/692536.
84. Ceddia RB, Somwar R, Maida A, Fang X, Bikopoulos G, Sweeney
G. Globular adiponectin increases GLUT4 translocation and glu-
cose uptake but reduces glycogen synthesis in rat skeletal muscle
cells. Diabetologia. 2005;48(1):132–9. doi:10.1007/s00125-004-
1609-y.
85. Liu Y, Chewchuk S, Lavigne C, Brule S, Pilon G, Houde V, et al.
Functional significance of skeletal muscle adiponectin production,
changes in animal models of obesity and diabetes, and regulation by
rosiglitazone treatment. Am J Physiol Endocrinol Metab.
2009;297(3):E657–664. doi:10.1152/ajpendo.00186.2009.
86. Wang Y, Zhou M, Lam KS, Xu A. Protective roles of adiponectin in
obesity-related fatty liver diseases: Mechanisms and therapeutic
implications. Arq Bras Endocrinol Metabol. 2009;53(2):201–12.
87. Ma K, Cabrero A, Saha PK, Kojima H, Li L, Chang BH, et al.
Increased beta -oxidation but no insulin resistance or glucose intol-
erance in mice lacking adiponectin. J Biol Chem. 2002;277(38):
34658–61. doi:10.1074/jbc.C200362200.
88. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M,
Nagaretani H, et al. Diet-induced insulin resistance in mice lacking
adiponectin/ACRP30. Nature medicine. 2002;8(7):731–7. doi:10.
1038/nm724.
89. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J,
et al. Disruption of adiponectin causes insulin resistance and
neointimal formation. J B iol Chem. 2002;277(29):25863–6.
doi:10.1074/jbc.C200251200.
90. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M,
et al. Targeted disruption of AdipoR1 and AdipoR2 causes abroga-
tion of adiponectin binding and metabolic actions. Nat Med.
2007;13(3):332–9. doi:10.1038/nm1557.
91. Bjursell M, Ahnmark A, Bohlooly YM, William-Olsson L, Rhedin
M, Peng XR, et al. Opposing effects of adiponectin receptors 1 and
2 on energy metabolism. Diabetes. 2007;56(3):583–93. doi:10.
2337/db06-1432.
92. Cleasby ME, Lau Q, Polkinghorne E, Patel SA, Leslie SJ, Turner N,
et al. The adaptor protein APPL1 increases glycogen accumulation
in rat skeletal muscle through activation of the PI3-kinase signaling
pathway. J Endocrinol. 2011. doi:10.1530/JOE-11-0039.
93. Tan Y, You H, Wu C, Altomare DA, Testa JR. Appl1 is dispensable
for mouse development, and loss of Appl1 has growth factor-
selective effects on Akt signaling in murine embryonic fibroblasts.
J Biol Chem. 2010;285(9):6377–89. doi:10.1074/jbc.M109.
068452.
94. Qiao L, Kinney B, Yoo HS, Lee B, Schaack J, Shao J. Adiponectin
increases skeletal muscle mitochondrial biogenesis by suppressing
mitogen-activated protein kinase phosphatase-1. [Research Support,
N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Diabetes.
2012;61(6):1463–70. doi:10.2337/db1 1-1475.
95. Civitarese AE, Ukropcova B, Carling S, Hulver M, DeFronzo RA,
Mandarino L, et al. Role of adiponectin in human skeletal muscle
bioenergetics. Cell Metab. 2006;4(1):75–87. doi:10.1016/j.cmet.
2006.05.002.
96. Vu V, R iddell MC , Sweeney G. Circulating adiponectin and
adiponectin receptor expression in skeletal muscle: Effects of exer-
cise. Diabetes Metab Res Rev. 2007;23(8):600–
11. doi:10.1002/
dmrr.778.
97. Marinho R, Ropelle ER, Cintra DE, De Souza CT, Da Silva AS,
Bertoli FC, et al. Endurance exercise training increases APPL1
expression and improves insulin signaling in the hepatic tissue of
diet-induced obese mice, independently of weight loss. [Research
Support, Non-U.S. Gov’t]. J Cell Physiol. 2012;227(7):2917–26.
doi:10.1002/jcp.23037.
98. Farias JM, Maggi RM, Tromm CB, Silva LA, Luciano TF, Marques
SO, et al. Exercise training performed simultaneously to a high-fat
diet reduces the degree of insulin resistance and improves adipoR1-
2/APPL1 protein levels in mice. [Research Support, Non-U.S.
Gov’t]. Lipids Health Dis. 2012;11:134. doi:10.1186/1476-511X-
11-134.
99. Ho lmes RM, Yi Z, De Filippis E, Berria R, Shahani S,
Sathyanarayana P, et al. Increased abundance of the adaptor protein
containing pleckstrin homology domain, phosphotyrosine binding
domain and leucine zipper motif (APPL1) in patients with obesity
and type 2 diabetes: evidence for altered adiponectin signaling.
Diabetologia. 2011. doi:10.1007/s00125-011-2173-x.
100. Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions
to current concepts of cancer metabolism. Nat Rev Cancer.
2011;11(5):325–37. doi:10.1038/nrc3038.
101. Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in
cancers by on cogenes and tumor supp ressor genes. Scien ce.
2010;330(6009):1340–4. doi:10.1126/science.1193494.
102. VanSaun MN. Molecular pathways: Adiponectin and leptin signal-
ing in cancer. Clin Cancer Res. 2013;19(8):1926–32. doi:10.1158/
1078-0432.ccr-12-0930.
103. Bergstrom A, Pisani P, Tenet V, Wolk A, Adami HO. Overweight as
an avoidable cause of cancer in Europe. International journal of
cancer. Journal international du cancer. 2001;91(3):421–30.
104. Kritchevsky D. Diet and cancer: What’s Next? The Journal of
nutrition. 2003;133(11):3827S–9S.
105. Shehzad A, Iqbal W, Shehzad O, Lee YS. Adiponectin: Regulation
of its production and its role in human diseases. Hormones (Athens).
2012;11(1):8–20.
106. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific
gene dysregulated in obesity. J Biol Chem. 1996;271(18):10697–
703. doi:10.1074/jbc.271.18.10697.
107. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen
BC, et al. Circulating concentrations of the adipocyte protein
adiponectin Are decreased in parallel with reduced insulin sensitiv-
ity during the progression to type 2 diabetes in rhesus monkeys.
Diabetes. 2001;50(5):1126–33. doi:10.2337/diabetes.50.5.1126.
108. Korner A, Pazaitou-Panayiotou K, Kelesidis T , Kelesidis I, Williams
CJ, Kaprara A, et al. Total and high-molecular-weight adiponectin in
breast cancer: In vitro and in vivo studies. Journal of Clinical
Endocrinology & Metabolism. 2007;92(3):1041–8. doi:10.1210/jc.
2006-1858.
109. Mantzoros C, Petridou E, Dessypris N, Chavelas C, Dalamaga M,
Alexe DM, et al. Adiponectin and breast cancer risk. Journal of
Clinical Endocrinology & Metabolism. 2004;89(3):1102–
7. doi:10.
1210/jc.2003-031804.
110. Miyoshi Y, Funahashi T, Kihara S, Taguchi T, Tamaki Y,
Matsuzawa Y, et al. Association of serum adiponectin levels with
breast cancer risk. Clin Cancer Res. 2003;9(15):5699–704.
111. Chen D-C, Chung Y-F, Yeh Y-T, Chaung H-C, Kuo F-C, Fu O-Y,
et al. Serum adiponectin and leptin levels in Taiwanese breast cancer
patients. Cancer letters. 2006;237(1):109–14.
112. Duggan C, Irwin ML, Xiao L, Henderson KD, Smith AW,
Baumgartner RN, et al. Associations of insulin resistance and
adiponectin with mortality in women with breast cancer. J Clin
Oncol. 2011;29(1):32–9. doi:10.1200/jco.2009.26.4473.
113. Dieudonne M-N, Bussiere M, Dos Santos E, Leneveu M-C, Giudicelli
Y, Pecquery R. Adiponectin mediates antiproliferative and apoptotic
responses in human MCF7 breast cancer cells. Biochem Biophys Res
Commun. 2006;345(1):271–9. doi:10.1016/j.bbrc.2006.04.076.
114. Grossmann ME, Nkhata KJ, Mizuno NK, Ray A, Cleary MP.
Effects of adiponectin on breast cancer cell growth and signaling.
Br J Cancer. 2008;98(2):370–9. doi:10.1038/sj.bjc.6604166.
115. Li G, Cong L, Gasser J, Zhao J, Chen K, Li F. Mechanisms
underlying the anti-proliferative actions of adiponectin in human
breast cancer cells, MCF7–Dependency on the cAMP/protein
kinase-a pathway. Nutrition and Cancer. 2010;63(1):80–8. doi:10.
1080/01635581.2010.516472.
Rev Endocr Metab Disord
116. Pfeiler GH, Buechler C, Neumeier M, Schaffler A, Schmitz G,
Ortmann O, et al. Adiponectin effects on human breast cancer cells
are dependent on 17-beta estradiol. Oncol Rep. 2008;19(3):787–93.
117. Taliaferro-Smith L, Nagalingam A, Knight BB, Oberlick E, Saxena
NK, Sharma D. Integral role of PTP1B in adiponectin-mediated
inhibition of oncogenic actions of leptin in breast carcinogenesis.
Neoplasia. 2013;15(1):23–38.
118. Nkhata KJ, Ray A, Schuster TF, Grossmann ME, Cleary MP.
Effects of adiponectin and leptin co-treatment on human breast
cancer cell growth. Oncol Rep. 2009;21(6):1611–9.
119. Kim KY, Baek A, Hwang JE, Choi YA, Jeong J, Lee MS, et al.
Adiponect in-ac tivated AM PK st imulates dephosphorylation o f
AKT through protein phosphatase 2A activation. Cancer Res.
2009;69(9):4018–26. doi:10.1158/0008-5472.can-08-2641.
120. Wang Y, Lam J B, Lam KS, Liu J, Lam MC, Ho o RL, et al.
Adiponectin modulates the glycogen synthase kinase-3beta/beta-
catenin signaling pathway and attenuates mammary tumorigenesis
of MDA-MB-231 cells in nude mice. Cancer Res. 2006;66
(23):11462–70. doi:10.1158/0008-5472.can-06-1969.
121. Liu J, Lam JB, Chow KH, Xu A, Lam KS, Moon RT, et al.
Adiponectin stimulates Wnt inhibitory factor-1 expression through
epigenetic regulations involving the transcription factor specificity
protein 1. Carcinogenesis. 2008;29(11):2195–202. doi:10.1093/
carcin/bgn194.
122. Lam JB, Chow KH, Xu A, Lam KS, Liu J, Wong NS, et al.
Adiponectin haploinsufficiency promotes mammary tumor devel-
opment in MMTV-PyVT mice by modulation of phosphatase and
tensin homolog activities. PLoS One. 2009;4(3):e4968. doi:10.
1371/journal.pone.0004968.
123. Vander Heiden MG, Cantley LC, Thompson CB. Understanding
the Warburg effect: The metabolic requirements of cell prolifera-
tion. Science. 2009;324(5930):1029–33. doi:10.1126/science.
1160809.
124. Boudeau JRM, Sapkota G, Alessi DR. LKB1, a protein kinase
regulating cell proliferation and polarity. FEBS Lett. 2003;
546(1):159–65. doi:10.1016/S0014-5793(03)00642-2.
125. Kyriakis JM. At the crossroads: AMP-activated kinase and the
LKB1 tumor suppressor link cell proliferation to metabolic regula-
tion. J Biol. 2003;2(4):26. doi:10.1186/1475-4924-2-26.
126. Inoki K, Zhu T, Guan K-L. TSC2 Mediates cellular energy response
to control cell growth and survival. Cell. 2003;115(5):577–90.
127. Kimura N, Tokunaga C, Dalal S, Richardson C, Yoshino K, Hara K,
et al. A possible linkage between AMP-activated protein kinase
(AMPK) and mammalian target of rapamycin (mTOR) signaling
pathway. Genes Cells. 2003;8(1):65–79.
128. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kos matka M,
DePinho RA, et al. The LKB1 tumor suppressor negatively regu-
lates mTOR signaling. Cancer cell. 2004;6(1):91–9.
129. Hardie DG. AMP-activated/SNF1 protein kinases: Conserved
guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8
(10):774–85. doi:10.1038/nrm2249.
130. Takahata C, Miyoshi Y, Irahara N, Taguchi T, Tamaki Y, Noguchi S.
Demonstration of adiponectin receptors 1 and 2 mRNA expression
in human breast cancer cells. Cancer Lett. 2007;250(2):229–36.
doi:10.1016/j.canlet.2006.10.006.
131. Karaduman M, Bilici A, Ozet A, Sengul A, Musabak U, Alomeroglu
M. Tissue levels of adiponectin in breast cancer patients. Med Oncol.
2007;24(4):361–6.
Rev Endocr Metab Disord
