5ʹ-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that
was originally identiﬁed as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has
identiﬁed diverse molecular mechanisms and physiological conditions that regulate the AMPK activity. AMPK regulates diverse
metabolic and physiological processes and is dysregulated in major chronic diseases, such as obesity, inﬂammation, diabetes
and cancer. On the basis of its critical roles in physiology and pathology, AMPK is emerging as one of the most promising
targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the
molecular and physiological regulation of AMPK and its metabolic and physiological functions. In addition, we discuss the
mechanisms underlying the versatile roles of AMPK in diabetes and cancer.
Experimental & Molecular Medicine (2016) 48, e245; doi:10.1038/emm.2016.81; published online 15 July 2016
MOLECULAR REGULATION OF 5ʹ-ADENOSINE
MONOPHOSPHATE (AMP)-ACTIVATED PROTEIN KINASE
The basic and emerging molecular mechanisms of AMPK
regulation are discussed below and summarized in Figure 1.
Basic mechanisms: adenylate charge, calcium and T172
AMPK is a heterotrimeric complex containing one catalytic
α-subunit and two regulatory β-andγ-subunits.1In mammals,
AMPK α-andβ-subunits have two isoforms each, and AMPK
γ-subunit has three isoforms. This suggests the presence of 12
potential combinations of AMPK, each with different functions
under different physiological conditions.2Several studies have
suggested that these isoforms of AMPK subunits behave and
are regulated differently under different physiological
conditions.2,3 AMPK is regulated both allosterically and by
post-translational modiﬁcations. The most well-deﬁned
mechanisms of AMPK activation are phosphorylation at
T172 of the α-subunit and by AMP and/or adenosine dipho-
sphate (ADP) binding to γ-subunit.4Adenosine triphosphate
(ATP) competitively inhibits the binding of both AMP and
ADP to the γ-subunit, which suggests that AMPK is a sensor of
AMP/ATP or ADP/ATP ratios.
Phosphorylation at T172 of the AMPK α-subunit is regu-
lated by at least three kinases and three phosphatases: namely,
liver kinase B1 (LKB1), which exists in a heterotrimeric
complex with STRAD and MO25; calcium-/calmodulin-depen-
dent kinase kinase 2 (CaMKK2); TGFβ-activated kinase 1
(TAK1); protein phosphatase 2A (PP2A); protein phosphatase
2C (PP2C) and Mg2+-/Mn2+-dependent protein phosphatase
1E (PPM1E).5–12 In energy-replete conditions, that is, in the
presence of low AMP/ATP and ADP/ATP ratios, phosphatases
can easily access T172 of the AMPK α-subunit to keep it in the
unphosphorylated state. However, when energy is depleted,
high levels of AMP and ADP bind to CBS3 of the AMPK
γ-subunit, which prevents the phosphatases from accessing
T172 of the AMPK α-subunit, thus increasing its phosphoryla-
tion. In addition, binding of AMP and (to a lesser extent) ADP
to CBS3 stimulates LKB1-mediated phosphorylation, which
requires myristoylation of the AMPK β-subunit.13 Finally, the
binding of AMP, but not of ADP, to CBS1 increases intrinsic
AMPK activity by inducing its allosteric activation. In addition
to the binding of adenylates, the binding of glycogen, especially
glycogen with high branch points, to the β-subunit inhibits
AMPK; however, the physiological signiﬁcance of this is
unclear.14 Intracellular calcium activates AMPK through
CaMKK2-mediated phosphorylation. TAK1, a MAPKKK
family member (MAP3K7), also phosphorylates and activates
AMPK; however, the physiological conditions under which the
TAK1–AMPK pathway operates remain to be elucidated.15,16
College of Pharmacy and Institute of Pharmaceutical Science and Technology, Ajou University, Gyeonggi-do, Republic of Korea
Correspondence: Professor S-M Jeon College of Pharmacy and Institute of Pharmaceutical Science and Technology, Ajou University, 206, World cup-ro,
Yeongtong-gu, Suwon, Gyeonggi-do 16499, Republic of Korea.
Received 13 April 2016; revised 23 April 2016; accepted 26 April 2016
Experimental & Molecular Medicine (2016) 48, e245; doi:10.1038/emm.2016.81
2016 KSBMB. All rights reserved 2092-6413/16
Phosphorylation. Insulin inhibits AMPK by inducing its direct
phosphorylation by AKT. AKT phosphorylates S485 of the
AMPK α1-subunit (S487 in humans) but does not phosphorylate
an equivalent site in the AMPK α2-subunit (S491), thus blocking
upstream kinases from phosphorylating T172.17 Interestingly, a
recent study showed that GSK3-induced phosphorylation at
T479 of the AMPK α1-subunit is required for the AKT-mediated
inhibition of AMPK and vice versa,suggestingthatanassociation
inhibition of AMPK.18 The satiety hormone leptin also inhibits
AMPK by inducing p70S6K-dependent phosphorylation at S491
of the α2-subunit.19 Furthermore, diacylglycerol (DAG), whose
levels increase during hyperglycemia and hyperlipidemia, inhibits
AMPK by inducing its direct phosphorylation by protein kinase
C (PKC). A recent study showed that speciﬁcally PKD1 (PKCμ),
one of the PKC isoforms, phosphorylates S491 of the AMPK α2-
subunit.20 Finally, protein kinase A (PKA) also inhibits AMPK by
phosphorylating S173 of the α1-subunit, which blocks upstream
kinases, such as LKB1 and CaMKK2, from phosphorylating
Ubiquitination/sumoylation. Ubiquitination inhibits AMPK
by inducing its degradation. CIDEA, a cell death-inducing
Figure 1 Molecular regulation of AMPK and LKB1. (a)Modiﬁcation of the AMPK α1 (top) and α2 (bottom) subunits by phosphorylation/
dephosphorylation, ubiquitination, sumoylation and oxidation/reduction. Pathways marked in red indicate α1- or α2-subunit-speciﬁc
modiﬁcations. Numbers of modiﬁed amino acids are based on human proteins, and numbers in parenthesis are those reported in the
original research (see text for details). (b)Modiﬁcation of the AMPK β1 (top) and β2 (bottom) subunits by myristoylation, ubiquitination,
sumoylation and glycogen binding. Pathways marked in red indicate β1- or β2-subunit-speciﬁcmodiﬁcations (see text for details).
(c)Modiﬁcation of the AMPK γ-subunit by AMP, ADP or ATP binding. Binding of AMP to CBS1 induces allosteric activation, and binding
of AMP or ADP to CBS3 induces T172 phosphorylation (see text for details). (d)Modiﬁcation and regulation of LKB1 by phosphorylation,
acetylation, ubiquitination, sumoylation and 4HNE adduction (see text for details). Arrow indicates activation, and bar-headed line
indicates inhibition. α/γ-BD, α/γ-subunit-binding domain; AID, autoinhibitory domain; β-BD, β-subunit-binding domain; CBM, carbohydrate-
binding module; CBS, cystathionine beta-synthase domain; NLS, nuclear localization signal.
AMPK regulation and function
Experimental & Molecular Medicine
DNA fragmentation factor 45-like effector (CIDE) family
protein, interacts with and ubiquitinates the AMPK β-subunit
in brown adipose tissue.22 However, the exact mechanisms
underlying this are unclear. In addition, both the testis-
restricted melanoma antigen MAGE-A3/6 and TRIM28 ubi-
quitin ligase complex ubiquitinate the AMPK α1-subunit and
are overexpressed in cancer cells, thus inducing its cancer-
speciﬁc degradation.23 WW domain-containing E3 ubiquitin
protein ligase 1 also mediates the degradation of the AMPK
α2-subunit through ubiquitination in the presence of high
glucose levels.24 A recent study showed that SUMO E3 ligase
PIAS4 catalyzes the sumoylation and inhibition of the AMPK
α1-subunit, which elicits speciﬁc activation of the mechanistic
target of rapamycin complex 1 (mTORC1).25 However,
sumoylation by PIASy, which speciﬁcally targets the AMPK
β2-subunit, also activates AMPK and antagonizes its CIDEA-
induced ubiquitination at the C-terminal of the β2-subunit.26
Oxidation. A growing body of evidence suggests that the
reactive oxygen species (ROS) regulate AMPK activity,
although the mechanism is controversial.27,28 Interestingly,
recent studies showed that oxidative stress and energy stress
differentially regulate AMPK activity through direct oxidation
at cysteine residues in AMPK. In HEK293 cells, hydrogen
peroxide activates AMPK through oxidation and S-glutathio-
nylation at C299/C304 of its α-subunit.29 However, the
oxidation at C130/C174 of the AMPK α-subunit induced by
H2O2produced by glucose deprivation inhibits AMPK by
promoting its aggregation and disrupting its interaction with
upstream kinases.30 The opposing effects of AMPK oxidation
by different sources of ROS seem to be dependent on the
abundance of nutrients and the antioxidant capacity of cells
because energy stress-induced oxidation and inhibition of
AMPK was reversed by the expression of antioxidant enzyme
Protein–protein interactions/subcellular localization.AMPK
activity can also be regulated by protein–protein interactions
and its subcellular distribution. Although the mechanism is
poorly understood, folliculin (FLCN), a tumor suppressor
associated with Birt–Hogg–Dube syndrome, and its binding
partners folliculin interacting protein-1 (FNIP-1) and -2
(FNIP-2) have been shown to interact with and inhibit
AMPK.31,32 Interestingly, FLCN deﬁciency promotes metabolic
transformation by activating the AMPK-peroxisome prolifera-
tor-activated receptor gamma coactivator 1α(PGC1α)-hypoxia
inducible factor 1αaxis.33 The sestrin family of proteins
interacts with AMPK and leads to the activation of the
AMPK-TSC2 signaling axis to inhibit mTORC1.34 In addition,
upon AMP-dependent conformational change of AMPK, the
scaffold protein axin promotes LKB1–AMPK complex forma-
tion, which enables efﬁcient phosphorylation and activation of
AMPK by LKB1 during energy stress.35
N-myristoylated AMPK β-subunit serves as a scaffolding
protein that recruits the AMPK α-andγ-subunits to intracel-
lular membranes, including the mitochondrial membranes, in
response to energy stress.36 The nuclear localization signal
(NLS) present in the α2-subunit, but not in the α1-subunit, is
critical for the nucleocytoplasmic translocation of AMPK,
suggesting that α1-subunit-containing AMPK mainly phos-
phorylates cytosolic substrates that regulate acute effects and
that α2-subunit-containing AMPK mainly phosphorylates
transcriptional machinery that regulates gene expression for
long-term effects.37 In neurons, the AMPK γ1-subunit prefer-
entially localizes to the nucleus compared to other AMPK
γ-subunits; however, the mechanisms underlying this translo-
cation have not been explored to date.38
LKB1 modiﬁcation. The classic view suggests that LKB1 is
constitutively active. However, accumulating data suggest that
LKB1 activity is regulated by various physiological stimuli that
induce post-translational modiﬁcations as summarized in
Figure 1d. Because LKB1 contains an NLS domain but not a
nuclear export domain, it is generally localized to the nucleus.
LKB1 activation occurs after it complexes with MO25 and
STRADα, which induces its nuclear export and phosphoryla-
tion of its downstream targets, including AMPK, in the cytosol.
LKB1 modiﬁcations that regulate its nucleocytoplasmic trans-
location for AMPK activation have been reported. PKCζ
phosphorylates S307/S428 (S399 for short form) of LKB1 and
exports it to the cytosol, which is essential for AMPK
activation.39–42 However, Fyn, a Src family non-receptor
tyrosine kinase, phosphorylates Y261/Y365 of LKB1 to inhibit
cytoplasmic translocation and AMPK activation.43 Importantly,
SIRT1, a class III NAD-dependent histone deacetylase, deace-
tylates K48 of LKB1 to induce its cytoplasmic localization and
AMPK activation.44 A recent study showed that metabolic
stress triggers sumoylation at K178 of LKB1, which is essential
for binding and phosphorylating AMPK.45 Skp2-dependent
ubiquitination at K63 of LKB1 activates LKB1 by maintaining
the integrity of the LKB1–STRAD–MO25 complex and subse-
quently activates AMPK.46 Interestingly, adduct formation
between K97 of LKB1 and 4HNE, a lipid peroxidation marker,
during oxidative stress inhibits LKB1, and in turn, AMPK.47,48
METABOLIC FUNCTIONS OF AMPK
The key metabolic functions of AMPK are discussed below and
summarized in Figure 2.
The ﬁrst known function of AMPK is the regulation of lipid
metabolism. AMPK inhibits de novo synthesis of fatty acids
(FAs), cholesterol and triglycerides (TGs), and activates FA
uptake and β-oxidation (FAO). AMPK inhibits FA synthesis
(FAS) by inducing the inhibitory phosphorylation of two
targets: (1) acetyl-coA carboxylase 1 (ACC1), which catalyzes
the rate-limiting step in FA synthesis by converting acetyl-coA
to malonyl-coA, and (2) sterol regulatory element-binding
protein 1c (SREBP1c), a transcription factor that promotes the
expression of multiple lipogenic enzymes, including ACC1 and
FA synthase.49,50 Excessive accumulation of FAs in cells are
stored as TGs. The ﬁrst committed step in TG synthesis is
AMPK regulation and function
Experimental & Molecular Medicine
catalyzed by glycerol-3-phosphate acyltransferase, which is
inhibited by AMPK; however, it is unclear whether AMPK
inhibits this step through direct phosphorylation or indirect
regulation.51 AMPK also inhibits cholesterol synthesis by
inducing the inhibitory phosphorylation of the rate-limiting
enzyme HMG-CoA reductase.52
In addition to the inhibition of lipid anabolism, AMPK
activates lipid catabolism. AMPK increases FA uptake by
controlling the translocation of FA transporter CD36 to the
plasma membrane; however, the mechanism underlying this is
unclear.53 Once inside cells, FAs are transported into the
mitochondria for β-oxidation by carnitine palmitoyltrans-
ferase-1 (CPT-1). AMPK increases CPT-1 activity and activates
FAO by inducing the inhibitory phosphorylation of ACC2,
which is localized to the outer membrane of the mitochondria
near CPT-1 where it inhibits production of malonyl-CoA, a
potent allosteric inhibitor of CPT-1.50 However, AMPK
inhibits lipolysis by inducing the inhibitory phosphorylation
of hormone-sensitive lipase in the adipose tissue.54 These data
suggest that the central role of AMPK in lipid metabolism
involves controlling the concentration of circulating free FAs
(FFAs) by activating FAO, and by inhibiting lipolysis and
In skeletal muscles, AMPK stimulates glucose uptake by
translocating GLUT4-containing intracellular vesicles across
the plasma membrane. Fusion of these vesicles with the plasma
membrane requires Rab family G proteins in their active
GTP-bound state. AMPK phosphorylates and inhibits the
Rab-GTPase-activating protein TBC1D1, which increases the
activity of Rab family G proteins and induces fusion of GLUT4
vesicles with the plasma membrane.56 Interestingly, a recent
study showed that AMPK also increases glucose uptake in
HEK293 cells by blocking endocytosis and by promoting
GLUT1 expression.57 AMPK-induced GLUT1 regulation is
mediated by the phosphorylation and degradation of TRX-
interacting protein, which induces GLUT1 internalization.
AMPK also increases the mRNA expression of the genes
encoding GLUT4 and hexokinase 2 to facilitate glucose
After glucose is transported into the cells, it is phosphory-
lated by hexokinases to generate glucose-6-phosphate. Glucose-
6-phosphate is then consumed in several metabolic pathways
including glycolysis, glycogen synthesis and pentose phosphate
pathway. Among these pathways, glycolysis and glycogen
synthesis are regulated by AMPK. Studies of cardiomyocytes,
Figure 2 Metabolic functions of AMPK. A schematic summarizing the mechanisms underlying AMPK-induced regulation of diverse
metabolic pathways. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).
AMPK regulation and function
Experimental & Molecular Medicine
macrophages/monocytes and tumor cells indicate that AMPK
stimulates glycolysis by phosphorylating and activating
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/3, which
produces fructose-2,6-bisphosphate, an allosteric activator
of glycolytic enzyme phosphofructokinase-1.60,61 AMPK inhibits
glycogen synthesis through inhibitory phosphorylation of
glycogen synthase (GS). However, chronic activation of AMPK
can indirectly increase glycogen synthesis by increasing glucose
uptake and glucose-6-phosphate production. This induces
allosteric activation of GS that can overcome inhibitory phos-
phorylation by AMPK.62 Furthermore, AMPK also activates
glycogen breakdown by phosphorylating and activating glycogen
Hepatic gluconeogenesis is important for maintaining blood
glucose levels. AMPK inhibits gluconeogenesis by inhibiting
several transcription factors, such as hepatocyte nuclear factor 4
(HNF4) and CREB regulated transcription coactivator 2
(CRTC2), that promote the expression of gluconeogenic
enzymes, including phosphoenolpyruvate carboxykinase and
glucose-6-phosphatase.63,64 In addition, AMPK can also inhibit
gluconeogenesis by phosphorylating and inducing the nuclear
exclusion of class IIa histone deacetylases, which normally
deacetylate and activate transcription factor FOXO in the
nucleus, which results in the expression of gluconeogenic
enzymes during fasting.65
Protein synthesis is a high energy process that is inhibited
during energy stress to conserve cellular ATP. AMPK inhibits
cap-dependent translation during both initiation and elonga-
tion steps by indirectly inhibiting mTORC1 through the
phosphorylation of TSC2 and raptor. Inhibition of mTORC1
activates 4EBP1 and inhibits p70S6K, thus inhibiting the
initiation of cap-dependent translation and ribosomal proteins,
respectively. AMPK also downregulates ribosomal RNA synth-
esis by inducing the inhibitory phosphorylation of transcription
initiation factor 1A.66 Furthermore, AMPK directly inhibits
translational elongation by phosphorylating and activating
eEF2K, which phosphorylates and inhibits eEF2.67 However,
expression of genes important for cell survival is also required
during energy stress.68 Interestingly, AMPK can perform these
functions by switching translation from cap-dependent to cap-
independent mechanisms. A recent study suggested that AMPK
stimulates cap-independent and IRES-dependent translation of
Hif-1αduring energy stress to induce the expression of genes
critical for cell survival.69
Autophagy and mitochondrial biogenesis
Autophagy is a lysosome-dependent self-digestive process that
maintains cellular integrity during nutrient deﬁciency. Recent
studies have shown that AMPK activates autophagy by directly
and indirectly activating ULK1, a mammalian homolog of
ATG1.70,71 First, AMPK directly phosphorylates and activates
ULK1 to induce autophagy. Second, AMPK indirectly activates
ULK1 by inhibiting mTORC1, which phosphorylates and
inhibits ULK1 to disrupt the ULK1–AMPK interaction. This
coordinated regulation of ULK1 and mTORC1 eliminates
damaged mitochondria and maintains mitochondrial integrity
during nutrient starvation.70,71 In addition, the ﬁndings that
FOXO upregulates expression of several autophagy inducers,
such as Bnip3, LC3 and ATG12, and that AMPK phosphor-
ylates and activates FOXO suggest that AMPK regulates
autophagy by activating FOXO. Maintenance of mitochondrial
integrity requires elimination of damaged mitochondria
through autophagy and the production of fresh mitochondria
through biogenesis. Moreover, autophagic degradation can
contribute to energy generation by providing substrates for
mitochondrial metabolism. Therefore, mitochondrial bio-
genesis is a crucial process for energy production and cellular
response during nutrient deﬁciency. Pharmacological and
genetic evidence indicates that AMPK regulates mitochondrial
biogenesis by regulating PGC1α, a cofactor that promotes the
transcription of nuclear-encoded mitochondrial genes.72–74 At
least four mechanisms have been proposed to be involved in
AMPK-induced PGC1αactivation: namely, direct phosphor-
ylation of PGC1α;75 activation of SIRT1-mediated deacetylation
of PGC1αthrough an increase in NAD+/NADH ratio; AMPK-
dependent increase in nicotinamide phosphoribosyltransferase
(NAMPT) expression76 or FAO77 and p38 MAPK-dependent
increase in PGC1αexpression.78 SIRT1 activates AMPK by
deacetylating LKB1,44 which suggests the presence of a positive
feedback loop between AMPK and SIRT1.
Because metabolism is interconnected with redox regulation,
AMPK has a crucial role in regulating antioxidant defense
during oxidative stress. AMPK upregulates several antioxidant
genes, such as those encoding superoxide dismutase and
uncoupling protein 2, which reduce superoxide levels and
thioredoxin (TRX), a disulﬁde reductase by phosphorylating
and activating FOXO.79,80 Recent studies have suggested that
NRF2, another transcription factor that is a master regulator of
antioxidant response, is a potential target of AMPK to induce
antioxidant defense.81,82 However, the mechanisms underlying
this have yet to be elucidated. Furthermore, AMPK maintains
NADPH levels by regulating FA metabolism through the
phosphorylation and inhibition of ACC1/2 during metabolic
stress.83 FA synthesis is a major NADPH-consuming process.
In contrast, FAO produces NADPH by increasing TCA cycle
metabolites malate and isocitrate, which are catabolized by the
NADPH-producing enzymes malic enzyme 1 (ME1) and
isocitrate dehydrogenase 1 (IDH1), respectively. Inhibition of
FAS and activation of FAO by the AMPK-ACC1/2 axis
detoxiﬁes ROS by maintaining NADPH and GSH levels. These
data suggest that AMPK regulates antioxidant defense through
both short- and long-term effects.
PHYSIOLOGICAL REGULATION OF AMPK
The physiological contexts that regulate AMPK activity and
their physiological consequences are discussed below and
summarized in Figure 3.
AMPK regulation and function
Experimental & Molecular Medicine
Accumulating data suggest that overnutrition and obesity are
critical risk factors for modern chronic diseases, including
insulin resistance, diabetes and cancer. Notably, the accumula-
tion of three major nutrients, glucose, FAs and amino acids are
suggested to suppress AMPK and contribute to insulin
resistance.84 High glucose levels inhibit AMPK through
mechanisms that do not affect the AMP/ATP ratio.85–87 First,
the reduced expression or indirect inhibition of SIRT1 by the
reduction of NAD+/NADH ratio inhibits the SIRT1–LKB1
pathway. Second, high glucose levels induce the accumulation
of DAG, a PKC activator that induces the inhibitory phos-
phorylation of S485/491 of the AMPK α-subunit. Moreover,
glycogen accumulation and PP2A activation in the presence of
high glucose inhibits AMPK. High levels of amino acids,
especially branched-chain amino acids, inhibit AMPK by
increasing ATP levels and by decreasing the AMP/ATP ratio;
however, data on this mechanism are inconsistent.88–90 Excess
saturated FAs inhibit AMPK by inducing the accumulation of
DAG and ceramides, which can activate PKC and PP2A,
respectively.91 Hyperinsulinemia accompanied by excessive
nutrient accumulation inhibits AMPK by inducing AKT-
mediated inhibitory phosphorylation at S485/491 of the AMPK
Leptin, the satiety and anti-obesity hormone secreted by
adipocytes in the presence of insulin, prevents overnutrition by
inhibiting AMPK in the hypothalamus to suppress appetite. In
contrast, leptin activates AMPK in peripheral tissues, such as
skeletal muscles, both directly by increasing the AMP/ATP ratio
and indirectly through the hypothalamus–central nervous
system axis involving the α-adrenergic signal.93 However,
mechanisms underlying leptin-induced differential regulation
of AMPK in the hypothalamus and peripheral tissues have not
been elucidated. Despite the important role of leptin in obesity
control and insulin sensitization, leptin resistance has been
reported in the skeletal muscles of obese individuals because of
the upregulation of SOCS3, which prevents leptin-induced
increase in the AMP/ATP ratio and activation of AMPK.94
Similar to leptin, an anti-obesity cytokine ciliary neurotrophic
factor suppresses appetite and activates peripheral FAO by
differentially regulating AMPK.95,96 Moreover, cytokine ciliary
neurotrophic factor differentially regulates AMPK and exerts its
physiological effects even in leptin-resistant muscles, suggesting
that it can be a promising therapeutic candidate for developing
Calorie restriction exerts many beneﬁcial effects against aging,
diabetes and cancer. In addition to its effect on the AMP/ATP
Figure 3 Physiological regulation of AMPK. A schematic summarizing the mechanisms underlying the regulation of AMPK activity under
diverse physiological and pathological conditions. Arrow indicates activation, and bar-headed line indicates inhibition (see text for details).
AMPK regulation and function
Experimental & Molecular Medicine
ratio, calorie restriction activates AMPK through multiple
mechanisms. First, calorie restriction increases the NAD+/NADH
ratio, which activates SIRT1, which in turn activates AMPK by
deacetylating and activating LKB1.44,97 Second, as opposed to
overnutrition discussed above, calorie restriction decreases
blood insulin levels that may activate AMPK by decreasing its
AKT-mediated inhibitory phosphorylation.84 Third, calorie
restriction stimulates adiponectin secretion from adipocytes
that activates AMPK in multiple tissues, including skeletal
muscles.98 Interestingly, adiponectin secretion is signiﬁcantly
reduced in obese individuals, which partially explains reduced
AMPK activity in these individuals.99 Importantly, it has been
proposed that adiponectin explains many beneﬁcial effects of
calorie restriction, including insulin sensitization through
activation of AMPK.100
Ghrelin, a hunger hormone that is secreted from the
stomach during calorie restriction, exerts central orexigenic
and peripheral metabolic effects that are antagonized by
leptin.101 Ghrelin activates AMPK in the hypothalamus by
promoting intracellular calcium-induced CaMKK2 activation
through the stimulation of food intake.101,102 In contrast,
ghrelin inhibits AMPK in the adipose tissue and liver by
exerting lipogenic and gluconeogenic effects.103 A recent study
suggested that ghrelin is essential for survival during severe
calorie restriction or fasting by maintaining blood glucose
Obesity and inﬂammation
Accumulating data suggest that chronic inﬂammation is a
critical risk factor of modern chronic diseases, including insulin
resistance, diabetes and cancer, and that obesity is a risk factor
of chronic inﬂammation. In macrophages and adipose tissue,
FFAs or lipid infusion can trigger the proinﬂammatory
response by binding to toll-like receptor 4, which induces
insulin resistance.105 Interestingly, compelling evidence has
indicated a negative association between obesity/inﬂammation
and AMPK.106 Consistently, a recent study showed that
reduced AMPK activity was associated with increased inﬂam-
mation in the visceral adipose tissue and whole-body insulin
resistance in morbidly obese individuals.107 Initial studies
suggested that the proinﬂammatory cytokine TNFαsuppressed
AMPK phosphorylation and activate increasing PP2C expres-
sion in the skeletal muscles, thus contributing to insulin
resistance.108 Consistently, lipid infusion stimulated the proin-
ﬂammatory response in the heart by upregulating IL6 and
SOSC3 expression, which decreased AMPK phosphorylation
and protein levels.109 A recent study showed that LPS, FFAs
and diet-induced obesity downregulated the expression of
LKB1 and phosphorylation of the AMPK α1-subunit, a major
isoform of the AMPK α-subunit, in the adipose tissues and
macrophages, suggesting that AMPK is suppressed by multiple
mechanisms.110 In addition to cytokines and FFAs, resistin is
involved in inﬂammation and insulin resistance. Resistin,
which is mainly secreted by macrophages and neutrophils in
humans during inﬂammation, promotes the proinﬂammatory
response and induces insulin resistance.111–113 Although
mechanisms underlying these effects of resistin are unclear, it
has been suggested that resistin-induced insulin resistance is
partially mediated by AMPK inhibition through the proin-
ﬂammatory signals that induce PP2C or SOSC3
expression.112,114,115 Another study showed that anti-
inﬂammatory stimuli induced by TGFβand IL10 activate
AMPK in macrophages; however, upstream kinases involved
in this activation have not been identiﬁed.116 TAK1 is one
possible kinase involved in the phosphorylation of AMPK
during the anti-inﬂammatory response; however, this warrants
Several studies suggest that AMPK exerts potent anti-
inﬂammatory effects, as summarized in Figure 2. Intensive
research using various cell types indicates that AMPK inhibits
inﬂammation by indirectly inhibiting NFκB, a key regulator of
innate immunity and inﬂammation. Although the mechanisms
underlying AMPK-induced inhibition of NFκB are not clearly
understood, multiple mechanisms that suppress the expression
of inﬂammatory genes, including activation of SIRT1, FOXO
and PGC1α, may be involved.117 Interestingly, emerging
evidence suggests that AMPK exerts anti-inﬂammatory effects
in immune cells by switching metabolism from glycolysis to
mitochondrial oxidative metabolism, such as FAO.106 Resting
lymphocytes depend on mitochondrial oxidative metabolism.
However, upon stimulation, metabolism in these cells is
switched to glycolysis, which is associated with AMPK inhibi-
tion and rapid cell proliferation. Similarly, a recent study
showed that switching from proinﬂammatory M1 macrophages
to anti-inﬂammatory M2 macrophages depends on AMPK and
FAO.118 These data suggest that AMPK has a key role in
improving inﬂammation and insulin sensitivity by
Exercise and muscle contraction
Exercise-induced muscle contraction exerts many beneﬁcial
effects on health, including an insulin-sensitizing effect, largely
through activation of AMPK. Muscle contraction is an energy-
demanding process that greatly increases ATP turnover by over
100-fold, and induces rapid accumulation of ADP and AMP in
an intensity-dependent manner.119 In addition, muscle con-
traction depolarizes T-tubules that induce calcium release from
the sarcoplasmic reticulum in muscle cells.120 Muscle
contraction-induced increases in energy stress and calcium
levels promote LKB1- and CaMKK2-mediated AMPK activa-
Because metabolism and calorie restriction are well-recognized
regulators of aging, several studies on aging have focused on
AMPK. Recent studies have shown that AMPK activation in
response to various stimuli, such as exercise and muscle
contraction, gradually declines during aging.121 Although
mechanisms underlying this have not been elucidated, it is
possible that the age-related increase in chronic inﬂammation
levels suppresses AMPK activation in aged tissues.122 Impor-
tantly, numerous studies have shown that AMPK plays a
AMPK regulation and function
Experimental & Molecular Medicine
crucial role in regulating longevity and calorie restriction-
induced lifespan extension in worms, fruit ﬂies, and rodents.
Intensive research has identiﬁed several key AMPK-regulated
pro-longevity pathways, including inhibition of CRTC-1/
CREB, NFκB, and mTORC1 and activation of SIRT1, NRF2,
FOXO1, and ULK1, which induce antioxidant defense,
anti-inﬂammation, and autophagy.121
ROLE OF AMPK IN DIABETES AND CANCER: LESSONS
FROM TWO OLD DRUGS
Type-2 diabetes is a metabolic syndrome caused by insulin
resistance that induces hyperglycemia, hyperinsulinemia and
hyperlipidemia. Intensive research has shown that prolonged
exposure to excessive nutrients is one of the critical risk factors
of insulin resistance.84 High FFAs can drive insulin resistance
through DAG accumulation and PKC activation, which
impairs insulin signaling by phosphorylating (IRS)-1/2, the
insulin receptor substrate in the skeletal muscles, adipocytes
and the liver.123,124 In addition, high amino acids (especially
BCAAs) and insulin elicit mTORC1 hyperactivity, which
impairs insulin signaling through p70S6K-induced IRS-1/2
phosphorylation.125,126 mTORC1 hyperactivity also elicits insu-
lin resistance through ER stress, which induces ROS generation
and chronic inﬂammation.125,127 Notably, FFAs can induce
chronic inﬂammation both directly by activating TLR4
signaling105 and indirectly through ER stress.128,129 Impor-
tantly, all these conditions are associated with reduced AMPK
activity (Figure 3). As shown in Figures 2 and 4, AMPK
activation improves insulin sensitivity by inhibiting lipogenesis
(ACC1, SREBP1c), protein synthesis (mTORC1) and lipolysis
(HSL), and by activating FAO (ACC2). These pathways are
associated with reduced inhibitory phosphorylation of IRS-1/2,
ER stress/ROS, FFAs and chronic inﬂammation. Indeed,
metformin, an indirect activator of AMPK, is the most
frequently prescribed antidiabetic drug for type-2 diabetic
patients. Therefore, AMPK-activating agents would be bene-
ﬁcial for both preventing and treating patients with type-2
Cancer: initiation and promotion vs progression and
Tumor suppressor LKB1 functions as an upstream kinase, and
mTORC1 functions as a downstream effector of AMPK.
Therefore, AMPK activation would be a promising therapeutic
strategy because it inhibits mTORC1. However, as extensively
discussed,2,27,130 the role of AMPK in cancer is complicated,
similar to a double-edged sword. Previous studies reported that
LKB1 is mutated in 20–30% of patients with cervical and lung
cancers. Recent cancer genomic studies reported that several
AMPK subunits are frequently overexpressed in cervical
and lung cancers.131,132 A recent study also showed that
Figure 4 Integrative role of AMPK in diabetes and cancer. This model describes the integrative role of AMPK in diabetes and cancer.
AMPK exerts anti-inﬂammatory effects largely by regulating FA metabolism, NFκB and ER stress, indicating that AMPK activators can be
used for both preventing and treating insulin resistance and diabetes. The anti-inﬂammatory effects of AMPK also prevent cancer by
inhibiting the cancer initiation and promotion stages. However, AMPK activation can also promote malignant conversion, progression and
metastasis by enabling metabolic adaptation of tumor cells. Arrow indicates activation, bar-headed line indicates inhibition (see text for
details). N, normal cells; I, initiated cells.
AMPK regulation and function
Experimental & Molecular Medicine
MAGE-A3/6 and TRIM28 E3 ubiquitin ligase, which are
overexpressed in many cancers, induce cancer-speciﬁcAMPK
degradation. In contrast, another study showed that SKP2-
driven LKB1 ubiquitination in cancer cells increases its activity
toward AMPK activation and promotes tumor growth.23,46 As
shown in Figure 4, one possible explanation for this discre-
pancy in the role of AMPK in cancer is the timing of
modiﬁcation, mutation, or overexpression of LKB1 or AMPK.
The theory of multistep carcinogenesis indicates that the tumor
initiation stage, which is characterized by the introduction of
DNA mutations in normal chromosomes, favors the formation
of a stressful and proinﬂammatory environment for inducing
genetic mutations.133 Inactivation of the LKB1–AMPK pathway
during this stage may facilitate both cell growth and prolifera-
tion by activating mTORC1 and anabolic pathways, and by
introducing genetic mutations through the augmentation of
oxidative stress and proinﬂammatory response, largely through
dysregulation of FA metabolism (Figure 4). In fact, this model
can be supported by a recent ﬁnding that LKB1 deﬁciency
promotes neutrophil recruitment and proinﬂammatory cyto-
kine production in the lung tumor microenvironment.134 After
the introduction of multiple genetic mutations and growth of
cells into large clones such as benign tumors, the cells need to
adapt and survive more severe metabolic and oxidative stress
and proinﬂammatory environments to completely transform
into malignant tumor cells (malignant conversion and progres-
sion stage). In such cases, activation of the LKB1–AMPK
pathway would be beneﬁcial for tumors because it promotes
metabolic adaptation. Interestingly, this is also largely achieved
by the regulation of FA metabolism, which contributes to the
maintenance of NADH and NADPH levels, increases ATP
levels and decreases ROS levels (Figure 4).
This view is supported by the ﬁndings that LKB1 deletion
results in the formation of benign intestinal polyps that are
resistant to transformation and that expression of the AMPK
α2-subunit is suppressed in grades I and II human gastric
cancers but increased in grades III and IV human gastric
cancers.135,136 This view also points out the conﬂicting roles of
FA metabolism in different tumor stages because FAO activa-
tion and FAS inhibition can prevent early stages but promote
late stages of carcinogenesis (Figure 4). However, this model
does not explain how tumor cells in the initiation stage that
harbor mutations in the gene encoding LKB1 survive malig-
nant conversion and progression, and develop into malignant
tumors. This could be explained by the possibility that
malignant transformation of tumor cells could be induced by
the co-occurrence of complementing genetic mutations or
activation of other AMPK-activating pathways involving
CaMKK2 or TAK1.27,130,137 Therefore, it is necessary to
distinguish between the roles of AMPK in cancer depending
on the stages of carcinogenesis. Moreover, this suggests that
AMPK activation is beneﬁcial for cancer prevention but not for
cancer treatment. Rather, AMPK inhibition could be used for
treating established cancers by inhibiting stress adaptation and
Lessons from two old drugs: anti-inﬂammation as a
converging point and key mechanism for preventing both
diabetes and cancer by AMPK activation
A recent study showed that salicylate, a natural product and
in vivo metabolite of the anti-inﬂammatory drug aspirin,
directly activates AMPK by binding to its β1-subunit.138 This
direct effect on AMPK activation could explain the anti-
inﬂammatory effect of aspirin. Moreover, a previous study
found that aspirin reduces circulating FFA and TG levels in
obese patients with type-2 diabetes and increases FAO during
fasting in healthy humans, which can be explained by the direct
effect of aspirin on AMPK activation.139,140 Interestingly,
aspirin exerts chemopreventive effects and is used for cancer
prevention.141 The critical role of AMPK in metabolism and
inﬂammation suggests that aspirin could be effective for
treating insulin resistance and diabetes through AMPK activa-
tion. In addition, anti-inﬂammatory effects of metformin by
activating AMPK have been reported.142 Moreover, an epide-
miological study showed that the use of metformin in diabetic
patients signiﬁcantly decreased the incidence of various
cancers.143,144 Notably, chronic inﬂammation is one of the
most critical and common risk factors of cancer and diabetes.
Thus, the results of studies on aspirin and metformin suggest
that AMPK-induced suppression of chronic inﬂammation
could be a key mechanism by which activation of AMPK can
prevent both diabetes and cancer (Figure 4).
Many studies have demonstrated that AMPK is inhibited in
many pathological conditions, such as inﬂammation, diabetes,
aging and cancer, and that activation of AMPK can be
beneﬁcial to treat such diseases. Importantly, emerging data
using the two old drugs known to activate AMPK suggest that
the beneﬁcial effects of AMPK activation can be largely
attributed to its anti-inﬂammatory effects. Notably, the anti-
inﬂammatory role of AMPK is mediated at least in part by the
regulation of FA metabolism (FAO↑/FAS↓). However, caution
is needed when considering the role of AMPK in cancer
because it performs both anti- and pro-tumorigenic roles,
depending in part on the regulation of FA metabolism. The
pro-tumorigenic role of AMPK involves promotion of meta-
bolic adaptation for cancer cell survival by regulating FA
metabolism to maintain ATP and ROS levels during metabolic
stress in the tumor microenvironment. Collectively, we pro-
pose two converging points, FA metabolism and inﬂammation,
in the mechanisms by which AMPK has a role in diabetes and
cancer. First, AMPK could be beneﬁcial for preventing both
diabetes and cancer by suppressing inﬂammation via modula-
tion of FA metabolism. Second, AMPK can promote late stages
of carcinogenesis through modulation of FA metabolism in
tumor cells to induce metabolic adaptation in a metabolically
stressful tumor microenvironment. Thus, AMPK activation is a
promising strategy for preventing both diabetes and cancer,
whereas AMPK inhibition is a novel therapeutic strategy to
treat established cancers.
AMPK regulation and function
Experimental & Molecular Medicine
CONFLICT OF INTEREST
Theauthordeclaresnoconﬂict of interest.
I thank Dr N. Hay for the helpful comments and discussion on the
manuscript. This work was supported by the grants from the National
R&D Program for Cancer Control, Ministry of Health & Welfare,
Republic of Korea (S2014-A0251-00001) and Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Science, ICT & Future Planning
1 Davies SP, Hawley SA, Woods A, Carling D, Haystead TA, Hardie DG.
Puriﬁcation of the AMP-activated protein kinase on ATP-gamma-sepharose
and analysis of its subunit structure. Eur J Biochem 1994; 223:
2 Dasgupta B, Chhipa RR. Evolving lessons on the complex role of AMPK in
normal physiology and cancer. Trends Pharmacol Sci 2016; 37:
3 Ross FA, Jensen TE, Hardie DG. Differential regulation by AMP and ADP
of AMPK complexes containing different gamma subunit isoforms.
Biochem J 2016; 473:189–199.
4 Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that
maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13:
5 Voss M, Paterson J, Kelsall IR, Martin-Granados C, Hastie CJ, Peggie MW
et al. Ppm1E is an in cellulo AMP-activated protein kinase phosphatase.
Cell Signal 2011; 23:114–124.
6 Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP et al.
Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and
MO25 alpha/beta are upstream kinases in the AMP-activated protein
kinase cascade. JBiol2003; 2:28.
7 Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D et al.
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade.
Curr Biol 2003; 13:2004–2008.
8 Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA
et al. The tumor suppressor LKB1 kinase directly activates AMP-activated
kinase and regulates apoptosis in response to energy stress. Proc Natl
Acad Sci USA 2004; 101:3329–3335.
9 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 mammalian cells. Cell Metab
10 HawleySA,PanDA,MustardKJ,RossL,BainJ,EdelmanAMet al.
Calmodulin-dependent protein kinase kinase-beta is an alternative upstream
kinase for AMP-activated protein kinase. Cell Metab 2005; 2:9–19.
11 Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA.
The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated
protein kinase kinases. JBiolChem2005; 280: 29060–29066.
12 Davies SP, Helps NR, Cohen PT, Hardie DG. 5′-AMP inhibits depho-
sphorylation, as well as promoting phosphorylation, of the AMP-activated
protein kinase. Studies using bacterially expressed human protein
phosphatase-2C alpha and native bovine protein phosphatase-2AC. FEBS
Lett 1995; 377:421–425.
13 Oakhill JS, Chen ZP, Scott JW, Steel R, Castelli LA, Ling N et al. Beta-
subunit myristoylation is the gatekeeper for initiating metabolic stress
sensing by AMP-activated protein kinase (AMPK). Proc Natl Acad Sci USA
2010; 107: 19237–19241.
14 McBride A, Ghilagaber S, Nikolaev A, Hardie DG. The glycogen-binding
domain on the AMPK beta subunit allows the kinase to act as a
glycogen sensor. Cell Metab 2009; 9:23–34.
15 Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M et al. A pivotal role
for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated
protein kinase energy-sensor pathway. Proc Natl Acad Sci USA 2006;
16 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; 281:25336–25343.
17 Hawley SA, Ross FA, Gowans GJ, Tibarewal P, Leslie NR, Hardie DG.
Phosphorylation by Akt within the ST loop of AMPK-alpha1 down-
regulates its activation in tumour cells. Biochem J 2014; 459:
18 Suzuki T, Bridges D, Nakada D, Skiniotis G, Morrison SJ, Lin JD et al.
Inhibition of AMPK catabolic action by GSK3. Mol Cell 2013; 50:
19 Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. p70S6
kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on
food intake. Cell Metab 2012; 16:104–112.
20 Coughlan KA, Valentine RJ, Sudit BS, Allen K, Dagon Y, Kahn BB et al.
PKD1 inhibits AMPKalpha2 through phosphorylation of serine 491 and
impairs insulin signaling in skeletal muscle cells. JBiolChem2016; 291:
21 Djouder N, Tuerk RD, Suter M, Salvioni P, Thali RF, Scholz R et al. PKA
phosphorylates and inactivates AMPKalpha to promote efﬁcient lipolysis.
EMBO J 2010; 29:469–481.
22 Qi J, Gong J, Zhao T, Zhao J, Lam P, Ye J et al. Downregulation of
AMP-activated protein kinase by Cidea-mediated ubiquitination and
degradation in brown adipose tissue. EMBO J 2008; 27:1537–1548.
23 Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou YH et al.
Degradation of AMPK by a cancer-speciﬁc ubiquitin ligase. Cell 2015;
24 Lee JO, Lee SK, Kim N, Kim JH, You GY, Moon JW et al. E3 ubiquitin
ligase, WWP1, interacts with AMPKalpha2 and down-regulates its expres-
sion in skeletal muscle C2C12 cells. JBiolChem2013; 288:
25 Yan Y, Ollila S, Wong IP, Vallenius T, Palvimo JJ, Vaahtomeri K et al.
SUMOylation of AMPKalpha1 by PIAS4 speciﬁcally regulates mTORC1
signalling. Nat Commun 2015; 6: 8979.
26 Rubio T, Vernia S, Sanz P. Sumoylation of AMPKbeta2 subunit enhances
AMP-activated protein kinase activity. Mol Biol Cell 2013; 24:1801–1811.
27 Jeon SM, Hay N. The double-edged sword of AMPK signaling in cancer
and its therapeutic implications. Arch Pharm Res 2015; 38:346–357.
28 Cardaci S, Filomeni G, Ciriolo MR. Redox implications of AMPK-mediated
signal transduction beyond energetic clues. J Cell Sci 2012; 125:
29 Zmijewski JW, Banerjee S, Bae H, Friggeri A, Lazarowski ER, Abraham E.
Exposure to hydrogen peroxide induces oxidation and activation of
AMP-activated protein kinase. JBiolChem2010; 285:33154–33164.
30 Shao D, Oka S, Liu T, Zhai P, Ago T, Sciarretta S et al. A redox-dependent
mechanism for regulation of AMPK activation by Thioredoxin1 during
energy starvation. Cell Metab 2014; 19:232–245.
31 Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A
et al. Folliculin encoded by the BHD gene interacts with a binding protein,
FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc
Natl Acad Sci USA 2006; 103: 15552–15557.
32 Possik E, Jalali Z, Nouet Y, Yan M, Gingras MC, Schmeisser K et al.
Folliculin regulates ampk-dependent autophagy and metabolic stress
survival. PLoS Genet 2014; 10: e1004273.
33 Yan M, Gingras MC, Dunlop EA, Nouet Y, Dupuy F, Jalali Z et al. The
tumor suppressor folliculin regulates AMPK-dependent metabolic trans-
formation. JClinInvest2014; 124:2640–2650.
34 Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect
genotoxic stress and mTOR signaling. Cell 2008; 134:451–460.
35 Zhang YL, Guo H, Zhang CS, Lin SY, Yin Z, Peng Y et al. AMP as a low-
energy charge signal autonomously initiates assembly of AXIN–AMPK–
LKB1 complex for AMPK activation. Cell Metab 2013; 18:546–555.
36 Liang J, Xu ZX, Ding Z, Lu Y, Yu Q, Werle KD et al. Myristoylation confers
noncanonical AMPK functions in autophagy selectivity and mitochondrial
surveillance. Nat Commun 2015; 6: 7926.
37 Suzuki A, Okamoto S, Lee S, Saito K, Shiuchi T, Minokoshi Y. Leptin
stimulates fatty acid oxidation and peroxisome proliferator-activated
receptor alpha gene expression in mouse C2C12 myoblasts by changing
the subcellular localization of the alpha2 form of AMP-activated
protein kinase. Mol Cell Biol 2007; 27:4317–4327.
38 Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF.
Cellular distribution and developmental expression of AMP-activated
protein kinase isoforms in mouse central nervous system. J. Neurochem
39 Xie Z, Dong Y, Scholz R, Neumann D, Zou MH. Phosphorylation of LKB1
at serine 428 by protein kinase C-zeta is required for metformin-enhanced
activation of the AMP-activated protein kinase in endothelial cells.
Circulation 2008; 117:952–962.
AMPK regulation and function
Experimental & Molecular Medicine
40 Xie Z, Dong Y, Zhang M, Cui MZ, Cohen RA, Riek U et al. Activation
of protein kinase C zeta by peroxynitrite regulates LKB1-dependent
AMP-activated protein kinase in cultured endothelial cells. JBiolChem
41 Zhu H, Moriasi CM, Zhang M, Zhao Y, Zou MH. Phosphorylation of serine
399 in LKB1 protein short form by protein kinase Czeta is required for its
nucleocytoplasmic transport and consequent AMP-activated protein
kinase (AMPK) activation. JBiolChem2013; 288:16495–16505.
42 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; 29:3582–3596.
43 Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC. Fyn-dependent
regulation of energy expenditure and body weight is mediated by tyrosine
phosphorylation of LKB1. Cell Metab 2010; 11:113–124.
44 Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the
acetylation status, cytosolic localization, and activity of LKB1. Possible
role in AMP-activated protein kinase activation. JBiolChem2008; 283:
45 Ritho J, Arold ST, Yeh ET. A critical SUMO1 modiﬁcation of LKB1 regulates
AMPK activity during energy stress. Cell Rep 2015; 12:734–742.
46 Lee SW, Li CF, Jin G, Cai Z, Han F, Chan CH et al. Skp2-dependent
ubiquitination and activation of LKB1 is essential for cancer cell survival
under energy stress. Mol Cell 2015; 57:1022–1033.
47 Calamaras TD, Lee C, Lan F, Ido Y, Siwik DA, Colucci WS. Post-translational
modiﬁcation of serine/threonine kinase LKB1 via adduction of the reactive
lipid species 4-hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly
inhibits kinase activity. JBiolChem2012; 287: 42400–42406.
48 Wagner TM, Mullally JE, Fitzpatrick FA. Reactive lipid species from
cyclooxygenase-2 inactivate tumor suppressor LKB1/STK11: cyclopente-
none prostaglandins and 4-hydroxy-2-nonenal covalently modify and
inhibit the AMP-kinase kinase that modulates cellular energy homeostasis
and protein translation. JBiolChem2006; 281:2598–2604.
49 Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B et al. AMPK
phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis
and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab
50 Hardie DG, Pan DA. Regulation of fatty acid synthesis and oxidation by the
AMP-activated protein kinase. Biochem Soc Trans 2002; 30:
51 Muoio DM, Seefeld K, Witters LA, Coleman RA. AMP-activated kinase
reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in
liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is
a novel target. Biochem J 1999; 338:783–791.
52 Carling D, Clarke PR, Zammit VA, Hardie DG. Puriﬁcation and character-
ization of the AMP-activated protein kinase. Copuriﬁcation of acetyl-CoA
carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase
activities. Eur J Biochem 1989; 186:129–136.
53 Habets DD, Coumans WA, El Hasnaoui M, Zarrinpashneh E, Bertrand L,
Viollet B et al. Crucial role for LKB1 to AMPKalpha2 axis in the regulation
of CD36-mediated long-chain fatty acid uptake into cardiomyocytes.
Biochim Biophys Acta 2009; 1791:212–219.
54 Garton AJ, Yeaman SJ. Identiﬁcation and role of the basal phosphorylation
site on hormone-sensitive lipase. Eur J Biochem 1990; 191:245–250.
55 Daval M, Diot-Dupuy F, Bazin R, Hainault I, Viollet B, Vaulont S et al.
Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes.
JBiolChem2005; 280: 25250–25257.
56 Taylor EB, An D, Kramer HF, Yu H, Fujii NL, Roeckl KS et al. Discovery of
TBC1D1 as an insulin-, AICAR-, and contraction-stimulated signaling
nexus in mouse skeletal muscle. JBiolChem2008; 283:9787–9796.
57 Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G et al. AMPK-
dependent degradation of TXNIP upon energy stress leads to enhanced
glucose uptake via GLUT1. Mol Cell 2013; 49:1167–1175.
58 Zheng D, MacLean PS, Pohnert SC, Knight JB, Olson AL, Winder WW
et al. Regulation of muscle GLUT-4 transcription by AMP-activated
protein kinase. J Appl Phy siol (19 85) 2001; 91:1073–1083.
59 Stoppani J, Hildebrandt AL, Sakamoto K, Cameron-Smith D, Goodyear LJ,
Neufer PD. AMP-activated protein kinase activates transcription of the
UCP3 and HKII genes in rat skeletal muscle. Am J Physiol Endocrinol
Metab 2002; 283: E1239–E1248.
60 Marsin AS, Bertrand L, Rider MH, Deprez J, Beauloye C, Vincent MF et al.
Phosphorylation and activation of heart PFK-2 by AMPK has a role in the
stimulation of glycolysis during ischaemia. Curr Biol 2000; 10:
61 Marsin AS, Bouzin C, Bertrand L, Hue L. The stimulation of glycolysis by
hypoxia in activated monocytes is mediated by AMP-activated protein
kinase and inducible 6-phosphofructo-2-kinase. JBiolChem2002; 277:
62 Hunter RW, Treebak JT, Wojtaszewski JFP, Sakamoto K. Molecular
mechanism by which AMP-activated protein kinase activation promotes
glycogen accumulation in muscle. Diabetes 2011; 60:766–774.
63 Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S et al. The
CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.
Nature 2005; 437:1109–1111.
64 Leclerc I, Lenzner C, Gourdon L, Vaulont S, Kahn A, Viollet B. Hepatocyte
nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the
young is a novel target of AMP-activated protein kinase. Diabetes 2001;
65 Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez
JG et al. Class IIa histone deacetylases are hormone-activated regulators
of FOXO and mammalian glucose homeostasis. Cell 2011; 145:
66 Hoppe S, Bierhoff H, Cado I, Weber A, Tiebe M, Grummt I et al. AMP-
activated protein kinase adapts rRNA synthesis to cellular energy supply.
Proc Natl Acad Sci USA 2009; 106:17781–17786.
67 Leprivier G, Remke M, Rotblat B, Dubuc A, Mateo AR, Kool M et al. The
eEF2 kinase confers resistance to nutrient deprivation by blocking
translation elongation. Cell 2013; 153:1064–1079.
68 Mizrachy-Schwartz S, Kravchenko-Balasha N, Ben-Bassat H, Klein S,
Levitzki A. Optimization of energy-consuming pathways towards rapid
growth in HPV-transformed cells. PLoS ONE 2007; 2:e628.
69 Mizrachy-Schwartz S, Cohen N, Klein S, Kravchenko-Balasha N, Levitzki
A. Up-regulation of AMP-activated protein kinase in cancer cell lines is
mediated through c-Src activation. JBiolChem2011; 286:
70 Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W
et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase
connects energy sensing to mitophagy. Science 2011; 331:456
71 Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate
autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol 2011;
72 O'Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jorgensen SB, Schertzer
JD et al. AMP-activated protein kinase (AMPK) beta1beta2 muscle null
mice reveal an essential role for AMPK in maintaining mitochondrial
content and glucose uptake during exercise. Proc Natl Acad Sci USA
2011; 108: 16092–16097.
73 Winder WW, Holmes BF, Rubink DS, Jensen EB, Chen M, Holloszy JO.
Activation of AMP-activated protein kinase increases mitochondrial
enzymes in skeletal muscle. J Appl Physiol (1985) 2000; 88:
74 Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1
family of transcription coactivators. Cell Metab 2005; 1:361–370.
75 Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein
kinase (AMPK) action in skeletal muscle via direct phosphorylation of
PGC-1alpha. Proc Natl Acad Sci USA 2007; 104: 12017–12022.
76 Fulco M, Cen Y, Zhao P, Hoffman EP, McBurney MW, Sauve AA et al.
Glucose restriction inhibits skeletal myoblast differentiation by activating
SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 2008; 14:
77 Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC et al.
AMPK regulates energy expenditure by modulating NAD+ metabolism and
SIRT1 activity. Nature 2009; 458:1056–1060.
78 Chaube B, Malvi P, Singh SV, Mohammad N, Viollet B, Bhat MK. AMPK
maintains energy homeostasis and survival in cancer cells via regulating
p38/PGC-1α-mediated mitochondrial biogenesis. Cell Death Discov 2015;
79 Greer EL, Oskoui PR, Banko MR, Maniar JM, Gygi MP, Gygi SP et al. The
energy sensor AMP-activated protein kinase directly regulates the mam-
malian FOXO3 transcription factor. J Biol Chem 2007; 282:
80 Li XN, Song J, Zhang L, LeMaire SA, Hou X, Zhang C et al. Activation of
the AMPK–FOXO3 pathway reduces fatty acid-induced increase in
intracellular reactive oxygen species by upregulating thioredoxin. Diabetes
81 Zimmermann K, Baldinger J, Mayerhofer B, Atanasov AG, Dirsch VM,
Heiss EH. Activated AMPK boosts the Nrf2/HO-1 signaling axis—arole
for the unfolded protein response. Free Radic Biol Med 2015; 88:
AMPK regulation and function
Experimental & Molecular Medicine
82 Naveira LN, Mercado N, Ito K. AMPK signalling regulates Nrf2 localization
and activity via sirtuins in a monocytic cell line. Eur Respir J 2011; 38:
83 Jeon S-M, Chandel NS, Hay N. AMPK regulates NADPH homeostasis to
promote tumour cell survival during energy stress. Nature 2012; 485:
84 Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. Nutrient excess in
AMPK downregulation and insulin resistance. J Endocrinol Diabete s Obes
2013; 1: 1008.
85 Coughlan KA, Balon TW, Valentine RJ, Petrocelli R, Schultz V, Brandon A
et al. Nutrient excess and AMPK downregulation in incubated skeletal
muscle and muscle of glucose infused rats. PLoS ONE 2015; 10:
86 Itani SI, Saha AK, Kurowski TG, Cofﬁn HR, Tornheim K, Ruderman NB.
Glucose autoregulates its uptake in skeletal muscle: involvement of AMP-
activated protein kinase. Diabetes 2003; 52:1635–1640.
87 Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ et al.
Increased malonyl-CoA and diacylglycerol content and reduced AMPK
activity accompany insulin resistance induced by glucose infusion in
muscle and liver of rats. Am J Physiol Endocrinol Metab 2006; 290:
88 Saha AK, Xu XJ, Lawson E, Deoliveira R, Brandon AE, Kraegen EW et al.
Downregulation of AMPK accompanies leucine- and glucose-induced
increases in protein synthesis and insulin resistance in rat
skeletal muscle. Diabetes 2010; 59:2426–2434.
89 Du M, Shen QW, Zhu MJ, Ford SP. Leucine stimulates mammalian target
of rapamycin signaling in C2C12 myoblasts in part through inhibition of
adenosine monophosphate-activated protein kinase. JAnimSci2007;
90 Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB.
Insulin resistance due to nutrient excess: is it a consequence of AMPK
downregulation? Cell Cycle 2011; 10:3447–3451.
91 Wu Y, Song P, Xu J, Zhang M, Zou MH. Activation of protein phosphatase
2A by palmitate inhibits AMP-activated protein kinase. JBiolChem2007;
92 Valentine RJ, Coughlan KA, Ruderman NB, Saha AK. Insulin inhibits
AMPK activity and phosphorylates AMPK Ser(4)(8)(5)/(4)(9)(1) through
Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch
Biochem Biophys 2014; 562:62–69.
93 Minokoshi Y, Kim Y-B, Peroni OD, Fryer LGD, Muller C, Carling D et al.
Leptin stimulates fatty-acid oxidation by activating AMP-activated
protein kinase. Nature 2002; 415:339–343.
94 Steinberg GR, McAinch AJ, Chen MB, O'Brien PE, Dixon JB, Cameron-
Smith D et al. The suppressor of cytokine signaling 3 inhibits leptin
activation of AMP-kinase in cultured skeletal muscle of obese humans.
J Clin Endocrinol Metab 2006; 91:3592–3597.
95 Watt MJ, Dzamko N, Thomas WG, Rose-John S, Ernst M, Carling D et al.
CNTF reverses obesity-induced insulin resistance by activating skeletal
muscle AMPK. Nat Med 2006; 12:541–548.
96 Steinberg GR, Watt MJ, Fam BC, Proietto J, Andrikopoulos S, Allen AM
et al. Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase
signaling in leptin-resistant obese mice. Endocrinology 2006; 147:
97 Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F et al.
AMPK and SIRT1: a long-standing partnership? Am J Physiol Endocrinol
Metab 2010; 298:E751–E760.
98 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. Nat Med 2002; 8:1288–1295.
99 Nigro E, Scudiero O, Monaco ML, Palmieri A, Mazzarella G, Costagliola C
et al. New insight into adiponectin role in obesity and obesity-related
diseases. Biomed Res Int 2014; 2014: 658913.
100 Zhu M, Miura J, Lu LX, Bernier M, DeCabo R, Lane MA et al. Circulating
adiponectin levels increase in rats on caloric restriction: the potential for
insulin sensitization. Exp Gerontol 2004; 39:1049–1059.
101 Andrews ZB. Central mechanisms involved in the orexigenic actions of
ghrelin. Peptides 2011; 32:2248–2255.
102 Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ
et al. Hypothalamic CaMKK2 contributes to the regulation of energy
balance. Cell Metab 2008; 7:377–388.
103 Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE et al.
Cannabinoids and ghrelin have both central and peripheral metabolic and
cardiac effects via AMP-activated protein kinase. JBiolChem2005; 280:
104 Li RL, Sherbet DP, Elsbernd BL, Goldstein JL, Brown MS, Zhao TJ.
Profound hypoglycemia in starved, ghrelin-deﬁcient mice is caused by
decreased gluconeogenesis and reversed by lactate or fatty acids. JBiol
Chem 2012; 287:17942–17950.
105 Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links
innate immunity and fatty acid-induced insulin resistance. JClinInvest
106 O'Neill LA, Hardie DG. Metabolism of inﬂammation limited by AMPK and
pseudo-starvation. Nature 2013; 493:346–355.
107 Gauthier MS, O'Brien EL, Bigornia S, Mott M, Cacicedo JM, Xu XJ et al.
Decreased AMP-activated protein kinase activity is associated with
increased inﬂammation in visceral adipose tissue and with whole-body
insulin resistance in morbidly obese humans. Biochem Biophys Res
Commun 2011; 404:382–387.
108 Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC
et al. Tumor necrosis factor alpha-induced skeletal muscle insulin
resistance involves suppression of AMP-kinase signaling. Cell Metab
109 Ko HJ, Zhang Z, Jung DY, Jun JY, Ma Z, Jones KE et al. Nutrient stress
activates inﬂammation and reduces glucose metabolism by suppressing
AMP-activated protein kinase in the heart. Diabetes 2009; 58:
110 Yang Z, Kahn BB, Shi H, Xue BZ. Macrophage alpha1 AMP-activated
protein kinase (alpha1AMPK) antagonizes fatty acid-induced inﬂamma-
tion through SIRT1. JBiolChem2010; 285: 19051–19059.
111 Jiang S, Park DW, Tadie JM, Gregoire M, Deshane J, Pittet JF et al.
Human resistin promotes neutrophil proinﬂammatory activation and
neutrophil extracellular trap formation and increases severity of acute
lung injury. JImmunol2014; 192:4795–4803.
112 Park HK, Qatanani M, Briggs ER, Ahima RS, Lazar MA. Inﬂammatory
induction of human resistin causes insulin resistance in
endotoxemic mice. Diabetes 2011; 60:775–783.
113 Bostrom EA, Tarkowski A, Bokarewa M. Resistin is stored in neutrophil
granules being released upon challenge with inﬂammatory stimuli.
Biochim Biophys Acta 2009; 1793:1894–1900.
114 Luo Z, Zhang Y, Li F, He J, Ding H, Yan L et al. Resistin induces insulin
resistance by both AMPK-dependent and AMPK-independent mechan-
isms in HepG2 cells. Endocrine 2009; 36:60–69.
115 Pirvulescu M, Manduteanu I, Gan AM, Stan D, Simion V, Butoi E et al.
A novel pro-inﬂammatory mechanism of action of resistin in human
endothelial cells: up-regulation of SOCS3 expression through STAT3
activation. Biochem Biophys Res Commun 2012; 422:321–326.
116 Sag D, Carling D, Stout RD, Suttles J. Adenosine 5'-monophosphate-
activated protein kinase promotes macrophage polarization to an anti-
inﬂammatory functional phenotype. J Immunol 2008; 181:8633–8641.
117 Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase
inhibits NF-kappaB signaling and inﬂammation: impact on healthspan
and lifespan. JMolMed(Berl.)2011; 89:667–676.
118 Galic S, Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR
et al. Hematopoietic AMPK beta1 reduces mouse adipose tissue macro-
phage inﬂammation and insulin resistance in obesity. J Clin Invest 2011;
119 Sahlin K, Tonkonogi M, Soderlund K. Energy supply and muscle fatigue
in humans. Acta Physiol Scand 1998; 162:261–266.
120 O'Neill HM. AMPK and exercise: glucose uptake and insulin sensitivity.
Diabetes Metab J 2013; 37:1–21.
121 Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) con-
trols the aging process via an integrated signaling network. Ageing Res
Rev 2012; 11:230–241.
122 Salminen A, Huuskonen J, Ojala J, Kauppinen A, Kaarniranta K,
Suuronen T. Activation of innate immunity system during aging: NF-kB
signaling is the molecular culprit of inﬂamm-aging. Ageing Res Rev 2008;
123 Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D
et al. Role of diacylglycerol activation of PKCtheta in lipid-induced muscle
insulin resistance in humans. Proc Natl Acad Sci USA 2014; 111:
124 Turban S, Hajduch E. Protein kinase C isoforms: mediators of reactive
lipid metabolites in the development of insulin resistance. FEBS Lett
125 Blagosklonny MV. TOR-centric view on insulin resistance and diabetic
complications: perspective for endocrinologists and gerontologists. Cell
Death Dis 2013; 4:e964.
AMPK regulation and function
Experimental & Molecular Medicine
126 Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling
and insulin resistance. Nat Rev Endocrinol 2014; 10:723–736.
127 Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin
resistance, and the metabolic syndrome. JClinInvest2013; 123:
128 Jiao P, Ma J, Feng B, Zhang H, Alan-Diehl J, Eugene-Chin Y et al. FFA-
induced adipocyte inﬂammation and insulin resistance: involvement of ER
stress and IKKβpathways. Obesity 2011; 19:483–491.
129 Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K. Obesity-induced
endoplasmic reticulum stress causes chronic inﬂammation in
adipose tissue. Sci Rep 2012; 2:799.
130 Jeon SM, Hay N. The dark face of AMPK as an essential tumor promoter.
Cell Logist 2012; 2:197–202.
131 Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al.
Integrative analysis of complex cancer genomics and clinical proﬁles
using the cBioPortal. Sci Signal 2013; 6:pl1.
132 Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al. The
cBio cancer genomics portal: an open platform for exploring multidimen-
sional cancer genomics data. Cancer Discov 2012; 2:401–404.
133 Barrett JC. Mechanisms of multistep carcinogenesis and carcinogen risk
assessment. Environ. Health Perspect 1993; 100:9–20.
134 Koyama S, Akbay EA, Li YY, Aref AR, Skoulidis F, Herter-Sprie GS et al.
STK11/LKB1 deﬁciency promotes neutrophil recruitment and proinﬂam-
matory cytokine production to suppress T-cell activity in the lung tumor
microenvironment. Cancer Res 2016; 76:999–1008.
135 Kim YH, Liang H, Liu X, Lee JS, Cho JY, Cheong JH et al. AMPKalpha
modulation in cancer progression: multilayer integrative analysis of the
whole transcriptome in Asian gastric cancer. Cancer Res 2012; 72:
136 Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE
et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis
but resistance to transformation. Nature 2002; 419:162–167.
137 Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J
et al. Co-occurring genomic alterations deﬁne major subsets of KRAS-
mutant lung adenocarcinoma with distinct biology, immune proﬁles, and
therapeutic vulnerabilities. Cancer Discov 2015; 5:860–877.
138 Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ
et al. The ancient drug salicylate directly activates AMP-activated
protein kinase. Science 2012; 336:918–922.
139 Hundal RS, Petersen KF, Mayerson AB, Randhawa PS, Inzucchi S,
Shoelson SE et al. Mechanism by which high-dose aspirin improves glucose
metabolism in type 2 diabetes. JClinInvest2002; 109: 1321–1326.
140 Meex RC, Phielix E, Moonen-Kornips E, Schrauwen P, Hesselink MK.
Stimulation of human whole-body energy expenditure by salsalate is
fueled by higher lipid oxidation under fasting conditions and by higher
oxidative glucose disposal under insulin-stimulated conditions. JClin
Endocrinol Metab 2011; 96:1415–1423.
141 Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P et al. Aspirin
and non-steroidal anti-inﬂammatory drugs for cancer prevention: an
international consensus statement. Lancet Oncol 2009; 10:501–507.
142 Saisho Y. Metformin and inﬂammation: its potential beyond glucose-
lowering effect. Endocr Metab Immune Disord Drug Targets 2015; 15:
143 Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD.
Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;
144 Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B
et al. Metformin and cancer risk in diabetic patients: a systematic review
and meta-anal ysis. Cancer Prev Res (Phila) 2010; 3:1451–
This work is licensed under a Creative Commons
Attribution-NonCommercial-NoDerivs 4.0 Inter-
national License. The images or other third party material in
this article are included in the article’s Creative Commons
license, unless indicated otherwise in the credit line; if the
material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to
reproduce the material. To view a copy of this license, visit
AMPK regulation and function
Experimental & Molecular Medicine