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Regulation and function of AMPK in physiology and diseases


Abstract and Figures

5'-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.
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and diseases
Sang-Min Jeon
5ʹ-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that
was originally identied as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has
identied 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, inammation, 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
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 modications. The most well-dened
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).512 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 signicance 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
TAK1AMPK 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
Emerging mechanisms
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 specically 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)Modication 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-specic
modications. Numbers of modied amino acids are based on human proteins, and numbers in parenthesis are those reported in the
original research (see text for details). (b)Modication 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-specicmodications (see text for details).
(c)Modication 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)Modication 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
S-M Jeon
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-
specic 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 specic activation of the mechanistic
target of rapamycin complex 1 (mTORC1).25 However,
sumoylation by PIASy, which specically 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
thioredoxin-1 (TRX1).30
Proteinprotein interactions/subcellular localization.AMPK
activity can also be regulated by proteinprotein interactions
and its subcellular distribution. Although the mechanism is
poorly understood, folliculin (FLCN), a tumor suppressor
associated with BirtHoggDube 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 deciency 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 LKB1AMPK complex forma-
tion, which enables efcient 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 modication. 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 modications 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 modications 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.3942 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 LKB1STRADMO25 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
The key metabolic functions of AMPK are discussed below and
summarized in Figure 2.
Lipid metabolism
The rst 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 rst committed step in TG synthesis is
AMPK regulation and function
S-M Jeon
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
Glucose metabolism
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
S-M Jeon
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
phosphorylase (GP).
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
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 deciency. 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 ULK1AMPK interaction. This
coordinated regulation of ULK1 and mTORC1 eliminates
damaged mitochondria and maintains mitochondrial integrity
during nutrient starvation.70,71 In addition, the ndings 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 deciency. Pharmacological and
genetic evidence indicates that AMPK regulates mitochondrial
biogenesis by regulating PGC1α, a cofactor that promotes the
transcription of nuclear-encoded mitochondrial genes.7274 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.
Redox regulation
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 disulde 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
detoxies ROS by maintaining NADPH and GSH levels. These
data suggest that AMPK regulates antioxidant defense through
both short- and long-term effects.
The physiological contexts that regulate AMPK activity and
their physiological consequences are discussed below and
summarized in Figure 3.
AMPK regulation and function
S-M Jeon
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.8587 First,
the reduced expression or indirect inhibition of SIRT1 by the
reduction of NAD+/NADH ratio inhibits the SIRT1LKB1
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.8890 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 hypothalamuscentral 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
anti-obesity drugs.
Calorie restriction
Calorie restriction exerts many benecial 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
S-M Jeon
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 signicantly
reduced in obese individuals, which partially explains reduced
AMPK activity in these individuals.99 Importantly, it has been
proposed that adiponectin explains many benecial 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 inammation
Accumulating data suggest that chronic inammation is a
critical risk factor of modern chronic diseases, including insulin
resistance, diabetes and cancer, and that obesity is a risk factor
of chronic inammation. In macrophages and adipose tissue,
FFAs or lipid infusion can trigger the proinammatory
response by binding to toll-like receptor 4, which induces
insulin resistance.105 Interestingly, compelling evidence has
indicated a negative association between obesity/inammation
and AMPK.106 Consistently, a recent study showed that
reduced AMPK activity was associated with increased inam-
mation in the visceral adipose tissue and whole-body insulin
resistance in morbidly obese individuals.107 Initial studies
suggested that the proinammatory 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-
ammatory 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 inammation and insulin resistance. Resistin,
which is mainly secreted by macrophages and neutrophils in
humans during inammation, promotes the proinammatory
response and induces insulin resistance.111113 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-
ammatory signals that induce PP2C or SOSC3
expression.112,114,115 Another study showed that anti-
inammatory stimuli induced by TGFβand IL10 activate
AMPK in macrophages; however, upstream kinases involved
in this activation have not been identied.116 TAK1 is one
possible kinase involved in the phosphorylation of AMPK
during the anti-inammatory response; however, this warrants
further investigation.
Several studies suggest that AMPK exerts potent anti-
inammatory effects, as summarized in Figure 2. Intensive
research using various cell types indicates that AMPK inhibits
inammation by indirectly inhibiting NFκB, a key regulator of
innate immunity and inammation. Although the mechanisms
underlying AMPK-induced inhibition of NFκB are not clearly
understood, multiple mechanisms that suppress the expression
of inammatory genes, including activation of SIRT1, FOXO
and PGC1α, may be involved.117 Interestingly, emerging
evidence suggests that AMPK exerts anti-inammatory 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 proinammatory M1 macrophages
to anti-inammatory M2 macrophages depends on AMPK and
FAO.118 These data suggest that AMPK has a key role in
improving inammation and insulin sensitivity by
regulating FAO.
Exercise and muscle contraction
Exercise-induced muscle contraction exerts many benecial
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-
tion, respectively.
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 inammation
levels suppresses AMPK activation in aged tissues.122 Impor-
tantly, numerous studies have shown that AMPK plays a
AMPK regulation and function
S-M Jeon
Experimental & Molecular Medicine
crucial role in regulating longevity and calorie restriction-
induced lifespan extension in worms, fruit ies, and rodents.
Intensive research has identied 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-inammation, and autophagy.121
Type-2 diabetes
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 inammation.125,127 Notably, FFAs can induce
chronic inammation 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 inammation. 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-
cial 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 2030% 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-inammatory 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-inammatory 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
S-M Jeon
Experimental & Molecular Medicine
MAGE-A3/6 and TRIM28 E3 ubiquitin ligase, which are
overexpressed in many cancers, induce cancer-specicAMPK
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
modication, 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 proinammatory environment for inducing
genetic mutations.133 Inactivation of the LKB1AMPK 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 proinammatory response, largely through
dysregulation of FA metabolism (Figure 4). In fact, this model
can be supported by a recent nding that LKB1 deciency
promotes neutrophil recruitment and proinammatory 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 proinammatory environments to completely transform
into malignant tumor cells (malignant conversion and progres-
sion stage). In such cases, activation of the LKB1AMPK
pathway would be benecial 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 ndings 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 conicting 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 benecial 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-inammation 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-inammatory drug aspirin,
directly activates AMPK by binding to its β1-subunit.138 This
direct effect on AMPK activation could explain the anti-
inammatory 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
inammation suggests that aspirin could be effective for
treating insulin resistance and diabetes through AMPK activa-
tion. In addition, anti-inammatory effects of metformin by
activating AMPK have been reported.142 Moreover, an epide-
miological study showed that the use of metformin in diabetic
patients signicantly decreased the incidence of various
cancers.143,144 Notably, chronic inammation 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 inammation
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 inammation, diabetes,
aging and cancer, and that activation of AMPK can be
benecial to treat such diseases. Importantly, emerging data
using the two old drugs known to activate AMPK suggest that
the benecial effects of AMPK activation can be largely
attributed to its anti-inammatory effects. Notably, the anti-
inammatory 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 inammation,
in the mechanisms by which AMPK has a role in diabetes and
cancer. First, AMPK could be benecial for preventing both
diabetes and cancer by suppressing inammation 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
S-M Jeon
Experimental & Molecular Medicine
Theauthordeclaresnoconict 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
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AMPK regulation and function
S-M Jeon
Experimental & Molecular Medicine
... The concentration-dependent biphasic effects of QTP on pAMPK (upregulation) and Cx43 (downregulation of transcription) appear to be inversely correlated. Transcription of Cx43 is regulated by AMPK signalling via histone deacetylase [38,39,57,58]. AMPK is regulated by cAMP-dependent protein kinase (PKA) and exchange protein directly activated by cAMP (EPAC) [57,59], which is a major second messenger downstream of 5-HT7R [26,60]. ...
... Transcription of Cx43 is regulated by AMPK signalling via histone deacetylase [38,39,57,58]. AMPK is regulated by cAMP-dependent protein kinase (PKA) and exchange protein directly activated by cAMP (EPAC) [57,59], which is a major second messenger downstream of 5-HT7R [26,60]. Therefore, the concentration-dependent effects of the subchronic administration of QTP on cAMP synthesis were determined. ...
... AMPK regulates energy homeostasis and the transcription processes of several ion channels via histone deacetylase [38,39,43,57,58]. The resemblance of the effect of QTP on AMPK signalling and the dose-dependent bell-shaped pattern on weight gain suggest the possibility that AMPK signalling contributes to the biphasic weight gain induced by QTP [42]. ...
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Recent pharmacological studies indicated that the modulation of tripartite-synaptic transmission plays important roles in the pathophysiology of schizophrenia, mood disorders and adverse reactions. Therefore, to explore the mechanisms underlying the clinical and adverse reactions to atypical antipsychotics, the present study determined the effects of the sub-chronic administration of quetiapine (QTP: 3~30 μM) on the protein expression of 5-HT7 receptor (5-HT7R), connexin43 (Cx43), cAMP level and intracellular signalling, Akt, Erk and adenosine monophosphate-activated protein kinase (AMPK) in cultured astrocytes and the rat hypothalamus, using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. QTP biphasically increased physiological ripple-burst evoked astroglial D-serine release in a concentration-dependent manner, peaking at 10 μM. QTP enhanced the astroglial signalling of Erk concentration-dependently, whereas both Akt and AMPK signalling’s were biphasically enhanced by QTP, peaking at 10 μM and 3 μM, respectively. QTP downregulated astroglial 5-HT7R in the plasma membrane concentration-dependently. Protein expression of Cx43 in astroglial cytosol and intracellular cAMP levels were decreased and increased by QTP also biphasically, peaking at 3 μM. The dose-dependent effects of QTP on the protein expression of 5-HT7R and Cx43, AMPK signalling and intracellular cAMP levels in the hypothalamus were similar to those in astrocytes. These results suggest several complicated pharmacological features of QTP. A therapeutically relevant concentration/dose of QTP activates Akt, Erk and AMPK signalling, whereas a higher concentration/dose of QTP suppresses AMPK signalling via its low-affinity 5-HT7R inverse agonistic action. Therefore, 5-HT7R inverse agonistic action probably plays important roles in the prevention of a part of adverse reactions of QTP, such as weight gain and metabolic complications.
... factors that control the transcription of autophagy-related (ATG) genes (10). AMPK is a key enzyme that regulates cellular energy state, growth, inflammation, and mitochondrial function (12,13). In the liver, AMPK is activated via phosphorylation of the AMPK α-subunit at residue T172 by the liver kinase B-1 (LKB1), a serine/threonine kinase which is also a tumor suppressor (16). ...
... Phosphorylation of ULK1 kinase plays a key role in the initial stages of autophagy (12,13,15). AMPK phosphorylates ULK1 at residues S317 and S555, leading to ULK1 activation and autophagy induction. ...
... AMPK phosphorylates ULK1 at residues S317 and S555, leading to ULK1 activation and autophagy induction. In contrast, mTOR inhibits autophagy by phosphorylating ULK1 at residue S757, preventing phosphorylation and activation of ULK1 by AMPK (12,15). While hepatic levels of total ULK1 were not statistically different between control and G6pt-/-mice, hepatic levels of p-ULK1-S317 and p-ULK1-S555 were decreased significantly in the G6pt-/mice compared to the controls (Fig. 3C). ...
Type Ib glycogen storage disease (GSD-Ib) is caused by a deficiency in the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the endoplasmic reticulum lumen, where the intraluminal G6P is hydrolyzed to glucose by glucose-6-phosphatase-α (G6Pase-α). Clinically, GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and a long-term risk of hepatocellular adenoma/carcinoma (HCA/HCC). Studies have shown that autophagy deficiency contributes to hepatocarcinogenesis. In this study, we show that G6PT deficiency leads to impaired hepatic autophagy evident from attenuated expression of many components of the autophagy network, decreased autophagosome formation, and reduced autophagy flux. The G6PT-deficient liver displayed impaired SIRT1 and AMP-activated protein kinase (AMPK) signaling, along with reduced expression of SIRT1, forkhead boxO3a (FoxO3a), liver kinase B-1 (LKB1), and the active p-AMPK. Importantly, we show that overexpression of either SIRT1 or LKB1 in G6PT-deficient liver restored autophagy and SIRT1/FoxO3a and LKB1/AMPK signaling. The hepatosteatosis in G6PT-deficient liver decreased SIRT1 expression. LKB1 overexpression reduced hepatic triglycerides levels, providing a potential link between LKB1/AMPK signaling upregulation and the increase in SIRT1 expression. In conclusion, downregulation of SIRT1/FoxO3a and LKB1/AMPK signaling underlies impaired hepatic autophagy which may contribute to HCA/HCC development in GSD-Ib. Understanding this mechanism may guide future therapies.
... Notably, our Search Tool for the Retrieval of Interacting Genes (STRING) analysis of the Spef2 protein revealed that Spef2 interacts with adenosine kinase (Adk; Figure S3B). Adk is a conserved phosphotransferase that converts adenosine into AMP, which stimulates Ampkα activity (45,46) by phosphorylation at its T172 residue. Also, previous research indicates that the Spef2 protein itself contains an adenylate kinase (AK) domain (47), which catalyzes the interconversion of adenine nucleotides [2 adenosine diphosphate (ADP) ↔ AMP + ATP] and maintains AMP-Ampkα signaling (48). ...
... Here, we first investigated the role of Ampkα on acinar cell necrosis, apoptosis, and inflammation in a rodent model of acute pancreatitis and associated lung injury. The serine/threonine kinase Ampkα negatively regulates pro-inflammatory NF-κB activity (46). In our in vivo rodent model, pharmacological Ampkα activation with the thienopyridone derivative A769662 (52) reduced acute pancreatitis severity, oxidative stress, necrosis, apoptosis, NF-kB-mediated inflammation, and the degree of associated lung injury. ...
... This is consistent with numerous previous studies showing the anti-inflammatory effects of Ampkα agonism in other animal models of inflammatory disease, including inflammatory liver fibrosis (53), cardiac inflammation (54), amyloid-β-induced neuroinflammation (55), adipose tissue inflammation (56), inflammation-driven muscle atrophy (57), and synovial tissue inflammation (58). Previous molecular research reports that Ampkα's negative regulation of NF-κB activity operates through its downstream intermediaries Sirt1, forkhead box O (Foxo), and peroxisome proliferatoractivated receptor gamma coactivator 1-alpha (Pgc1α) (46). Accordingly, we found that pharmacological Ampkα activation stimulated anti-inflammatory Sirt1 upregulation in acinar cells. ...
Background: Pancreatic acinar cells are susceptible to nuclear factor kappa B (NF-κB)-mediated inflammation and resulting cell necrosis during early acute pancreatitis. As adenosine monophosphate-activated protein kinase alpha (Ampkα)/sirtuin 1 (Sirt1) pathway activity attenuates NF-κB activity, we examined whether the Ampkα/Sirt1 axis affects the progression of acute pancreatitis and associated lung injury in vivo. Furthermore, we explored the role of the ciliary protein sperm flagellar 2 (Spef2, Kpl2) in regulating Ampkα/Sirt1 activity in vitro and in vivo. Methods: Pancreatic injury, oxidative stress, acinar cell necrosis and apoptosis, acinar levels of Ampkα/Sirt1/NF-κB signaling activity, NF-kB-mediated inflammatory markers, and markers of associated lung injury were measured in rat models of acute pancreatitis following pharmacological Ampkα activation with A769662 or self-complementary recombinant adeno-associated virus serotype 6 (scAAV6)-mediated Spef2 overexpression. Additional in vivo rescue studies involving Ampkα silencing and/or constitutively active (CA)-Sirt1 overexpression were performed in acute pancreatitis rats. In vitro immunoblotting and Ampkα activity assays were conducted in the pancreatic acinar cell line AR42J. Results: Pharmacological Ampkα activation or Spef2 overexpression reduced acute pancreatitis severity, oxidative stress, necrosis, apoptosis, NF-kB-mediated inflammatory markers, and the degree of associated lung injury. Spef2 overexpression in AR42J cells in vitro promoted AmpkαThr172 phosphorylation and Ampkα activity. In vivo rescue studies revealed that Spef2's suppressive effect on acute pancreatitis and associated lung injury is mediated via the Ampkα/Sirt1 axis. Conclusions: This study established the existence of a Spef2/Ampkα/Sirt1 axis in pancreatic acinar cells that is involved in the regulation of NF-κB-mediated acinar cell inflammation and resulting cell necrosis during acute pancreatitis.
... AMPK is activated by cellular stress and a decrease in ATP production, which occurs with the inhibition of oxidative phosphorylation. A549 cells lack LKB1, which phosphorylates AMPK α-subunit at T172 leading to activation 27 . Allosteric activation of AMPK can occur without LKB1 27 . ...
... A549 cells lack LKB1, which phosphorylates AMPK α-subunit at T172 leading to activation 27 . Allosteric activation of AMPK can occur without LKB1 27 . Ym155 induced phosphorylation of AMPK at T172 indicating activation in H1299 cells but not in A549 cells (Fig. 6B). ...
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The imidazolium compound Ym155 was first reported to be a survivin inhibitor. Ym155 potently induces cell death of many types of cancer cells in preclinical studies. However, in phase II clinical trials Ym155 failed to demonstrate a significant benefit. Studies have suggested that the cytotoxic effects of Ym155 in cancer cells are not mediated by the inhibition of survivin. Understanding the mechanism by which Ym155 induces cell death would provide important insight how to improve its efficacy as a cancer therapeutic. We demonstrate a novel mechanism by which Ym155 induces cell death by localizing to the mitochondria causing mitochondrial dysfunction. Our studies suggest that Ym155 binds mitochondrial DNA leading to a decrease in oxidative phosphorylation, decrease in TCA cycle intermediates, and an increase in mitochondrial permeability. Furthermore, we show that mitochondrial stress induced by Ym155 and other mitochondrial inhibitors activates AMP-activated kinase leading to the downregulation to bone morphogenetic protein (BMP) signaling. We provide first evidence that Ym155 initiates cell death by disrupting mitochondrial function.
... Most neurodegenerative diseases are characterized by intracellular or extracellular aggregation of misfolded proteins, such as Aβ and tau in AD, α-synuclein in PD, huntingtin in HD and transactive response DNA-binding protein-43 (TDP-43) in amyotrophic lateral sclerosis (ALS) [111]. In the complex network of autophagy regulatory pathways, mTORC and AMPK signaling pathways serve as central nodes, integrating the metabolic signals and energy states of cells [112,113]. mTORC1 prevents autophagy mainly through suppressing phosphorylation of unc-51-like autophagy-activating kinase 1/2 (ULK1/2) and class III phosphatidylinositol 3-kinase (class III PtdIns3K complexes) [112]. The phosphorylation of its substrate RPS6KB1/S6K at Thr389 is a common marker for mTORC1 activity [112]. ...
... AMPK not only acts on the ULK1/2 and class III PtdIns3K complexes but also inhibits mTORC1 activity [114,115]. Phosphorylation on Thr172 of the AMPK catalytic subunit alpha and ACC on Ser79 are two common indicators of AMPK activity [113]. As mentioned above, metformin mainly influences neurodegenerative diseases such as AD. ...
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Metformin is a first-line drug for treating type 2 diabetes mellitus (T2DM) and one of the most commonly prescribed drugs in the world. Besides its hypoglycemic effects, metformin also can improve cognitive or mood functions in some T2DM patients; moreover, it has been reported that metformin exerts beneficial effects on many neurological disorders, including major depressive disorder (MDD), Alzheimer’s disease (AD) and Fragile X syndrome (FXS); however, the mechanism underlying metformin in the brain is not fully understood. Neurotransmission between neurons is fundamental for brain functions, and its defects have been implicated in many neurological disorders. Recent studies suggest that metformin appears not only to regulate synaptic transmission or plasticity in pathological conditions but also to regulate the balance of excitation and inhibition (E/I balance) in neural networks. In this review, we focused on and reviewed the roles of metformin in brain functions and related neurological disorders, which would give us a deeper understanding of the actions of metformin in the brain.
... SV40 ST antigen can activate the AKT pathway, increasing glucose uptake and aerobic glycolysis (24,30). The AMP-activated protein kinase Accepted Article (AMPK) acts as a cellular energy sensor, when loss of AMPK signaling occurs, it inhibits mTOR that is responsible for the activation of glucose uptake and glycolysis (31). Increased AMP/ATP activates AMPK; and mostly promotes ATP production by increasing nutrient catabolism (32). ...
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Viruses as intracellular pathogens hijack the host metabolism and reprogram to facilitate optimal virus production. DNA viruses can cause alterations in several metabolic pathways, including aerobic glycolysis also known as the Warburg effect, pentose phosphate pathway (PPP) activation, and amino acid catabolism such as glutaminolysis, nucleotide biosynthesis, lipid metabolism, and amino acid biosynthesis. The available energy for productive infection can be increased in infected cells via modification of different carbon source utilization. This review discusses the metabolic alterations of the DNA viruses that will be the basis for future novel therapeutic approaches.
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There is still an unmet need for development of safer antimelanogenic or melanin-degrading agents for skin hyperpigmentation, induced by intrinsic or extrinsic factors including aging or ultraviolet irradiation. Owing to the relatively low cytotoxicity compared with other chemical materials, several studies have explored the role of 2'-fucosyllactose (2'-FL), the most dominant component of human milk oligosaccharides. Here, we showed that 2'-FL reduced melanin levels in both melanocytic cells and a human skin equivalent three-dimensional in vitro model. Regarding the cellular and molecular mechanism, 2'-FL induced LC3I conversion into LC3II, an autophagy activation marker, followed by the formation of LC3II+/PMEL+ autophagosomes. Comparative transcriptome analysis provided a comprehensive understanding for the up- and downstream cellular processes and signaling pathways of the AMPK–ULK1 signaling axis triggered by 2'-FL treatment. Moreover, 2'-FL activated the phosphorylation of AMPK at Thr172 and of ULK1 at Ser555, which were readily reversed in the presence of dorsomorphin, a specific AMPK inhibitor, with consequent reduction of the 2'-FL-mediated hypopigmentation. Taken together, these findings demonstrate that 2'-FL promotes melanin degradation by inducing autophagy through the AMPK–ULK1 axis. Hence, 2'-FL may represent a new natural melanin-degrading agent for hyperpigmentation.
Polycystic ovary syndrome (PCOS) is a well-known reproductive syndrome usually associated with obesity, insulin resistance, and hyperinsulinemia. Although the first signs of PCOS begin early in adolescence, it is underexplored whether peripubertal obesity predisposes women to PCOS metabolic disturbances. To highlight that, we examined the impact of postnatal overfeeding-induced obesity, achieved by litter size reduction during the suckling period, on metabolic disturbances associated with visceral and subcutaneous adipose tissue (VAT and SAT) function in the 5α-dihydrotestosterone (5α-DHT)-induced animal model of PCOS. We analyzed markers of insulin signaling, lipid metabolism, and energy sensing in the VAT and SAT. Our results showed that postnatally overfed DHT-treated Wistar rats had increased VAT mass with hypertrophic adipocytes, together with hyperinsulinemia and increased HOMA index. In the VAT of these animals, insulin signaling remained unchanged while lipogenic markers decreased, which was accompanied by increased AMPK activation. In the SAT of the same animals, markers of lipogenesis and lipolysis increased, while the activity of AMPK decreased. Taken together, obtained results showed that postnatal overfeeding predisposes development of PCOS systemic insulin resistance, most likely as a result of worsened metabolic function of SAT, while VAT preserved its tissue insulin sensitivity through increased activity of AMPK.
Though icariside E4 (IE4) is known to have anti-noceptive, anti-oxidant, anti-Alzheimer and anti-inflammatory effects, there was no evidence on the effect of IE4 on lipid metabolism so far. Hence, the hypolipogenic mechanism of IE4 was investigated in HepG2 hepatocellular carcinoma cells (HCCs) in association with MID1 Interacting Protein 1(MID1IP1) and AMPK signaling. Here, IE4 did not show any toxicity in HepG2 cells, but reduced lipid accumulation in HepG2 cells by Oil Red O staining. MID1IP1 depletion decreased the expression of SREBP-1c and fatty acid synthase (FASN) and induced phosphorylation of ACC in HepG2 cells. Indeed, IE4 activated phosphorylation of AMPK and ACC and inhibited the expression of MID1IP1 in HepG2 cells. Furthermore, IE4 suppressed the expression of SREBP-1c, liver X receptor-α (LXR), and FASN for de novo lipogenesis in HepG2 cells. Interestingly, AMPK inhibitor compound C reversed the ability of IE4 to reduce MID1IP1, SREBP-1c, and FASN and activate phosphorylation of AMPK/ACC in HepG2 cells, indicating the important role of AMPK/ACC signaling in IE4-induced hypolipogenic effect. Taken together, these findings suggest that IE4 has hypolipogenic potential in HepG2 cells via activation of AMPK and inhibition of MID1IP1 as a potent candidate for treatment of fatty liver disease.
AMP-activated protein kinase (AMPK) and sirtuins are fuel-sensing enzymes. AMPK is activated upon increased AMP/ATP ratio, and sirtuins activation increases by increased NAD⁺ levels. There are seven isoforms of sirtuin (SIRT1-SIRT7) expressed at different cellular compartments. The most studied sirtuin isoform in the context of aging is SIRT1. SIRT1 and AMPK pathways are correlated and might have coexisted during evolution. They are involved in various age-related processes as they share common cellular targets. Multiple studies have revealed that increased AMPK and sirtuin activity can extend the lifespan of an organism. However, with age, the responsiveness of AMPK and SIRT1 reduces, which affects mitochondrial function, metabolism, increases oxidative stress and promotes inflammation. Increased activity of AMPK and SIRT1 has antiaging effects as observed in different species, and therefore they are believed to serve as potential therapeutic targets to treat age-related disorders. AMPK and SIRT1 activators are considered promising treatment approaches for diabetes, metabolic and mitochondrial disorders, and neurodegeneration. However, the mechanism of action of AMPK and sirtuin modulators is a subject of future research, and rigorous validation of these compounds are required before exploiting these compounds in the treatment of age-associated disorders.
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STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether inactivation of tumor suppressor genes such as STK11/LKB1 exert similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T cell suppressive effects, along with a corresponding increase in the expression of T cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1 inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1 targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL-6 neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1 mutated tumors with PD-1 targeting antibody therapies.
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AMP-activated protein kinase (AMPK) is an energy-sensing enzyme whose activity is inhibited in settings of insulin resistance. Exposure to a high glucose concentration has recently been shown to increase phosphorylation of AMPK at Ser485/491 of its α1/α2 subunit; however, the mechanism by which it does so is not known. Diacylglycerol (DAG), which is also increased in muscle exposed to high glucose, activates a number of signaling molecules including protein kinase (PK)C and PKD1. We sought to determine whether PKC or PKD1 is involved in inhibition of AMPK by causing Ser485/491 phosphorylation in skeletal muscle cells. C2C12 myotubes were treated with the PKC/D1 activator phorbol 12-myristate 13-acetate (PMA), which acts as a DAG mimetic. This caused dose- and time-dependent increases in AMPK Ser485/491 phosphorylation, which was associated with a ~60% decrease in AMPKα2 activity. Expression of a phosphodefective AMPKα2 mutant (S491A) prevented the PMA-induced reduction in AMPK activity. Serine phosphorylation and inhibition of AMPK activity were partially prevented by the broad PKC inhibitor Gӧ6983 and fully prevented by the specific PKD1 inhibitor CRT0066101. Genetic knockdown of PKD1 also prevented Ser485/491 phosphorylation of AMPK. Inhibition of previously identified kinases that phosphorylate AMPK at this site (Akt, S6K, and ERK) did not prevent these events. PMA treatment also caused impairments in insulin-signaling through Akt, which were prevented by PKD1 inhibition. Finally, recombinant PKD1 phosphorylated AMPKα2 at Ser491 in cell-free conditions. These results identify PKD1 as a novel upstream kinase of AMPKα2 Ser491 that plays a negative role in insulin signaling in muscle cells.
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Cancer cells exhibit unique metabolic response and adaptation to the fluctuating microenvironment, yet molecular and biochemical events imprinting this phenomenon are unclear. Here, we show that metabolic homeostasis and adaptation to metabolic stress in cancer cells are primarily achieved by an integrated response exerted by the activation of AMPK. We provide evidence that AMPK-p38-PGC-1α axis, by regulating energy homeostasis, maintains survival in cancer cells under glucose-limiting conditions. Functioning as a molecular switch, AMPK promotes glycolysis by activating PFK2, and facilitates mitochondrial metabolism of non-glucose carbon sources thereby maintaining cellular ATP level. Interestingly, we noted that AMPK can promote oxidative metabolism via increasing mitochondrial biogenesis and OXPHOS capacity via regulating expression of PGC-1α through p38MAPK activation. Taken together, our study signifies the fundamental role of AMPK in controlling cellular bioenergetics and mitochondrial biogenesis in cancer cells.
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AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of AMPKα1 attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPKα1 SUMOylation and the inhibition of AMPKα1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPKα1 mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKα-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPKα1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.
AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. AMPK executes numerous cellular functions, some of which are often perceived at odds with each other. While AMPK is essential for embryonic growth and development, its full impact in adult tissues is revealed under stressful situations that organisms face in the real world. Conflicting reports about its cellular functions, particularly in cancer, are intriguing and a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. Whether these drugs will have only context-specific benefits or detrimental effects in the treatment of human cancer will be a subject of intense research. Here we review the current state of AMPK research with an emphasis on cancer and discuss the yet unresolved context-dependent functions of AMPK in human cancer.
The g subunits of heterotrimeric AMPK complexes contain the binding sites for the regulatory adenine nucleotides AMP, ADP and ATP. We addressed whether complexes containing different g isoforms display different responses to adenine nucleotides by generating cells stably expressing FLAG-tagged versions of the g1, g2 or g3 isoform. When assayed at a physiological ATP concentration (5 mM), g1- and g2-containing complexes were allosterically activated almost 10-fold by AMP, with EC50 values one to two orders of magnitude lower than the ATP concentration. By contrast, g3 complexes were barely activated by AMP under these conditions, although we did observe some activation at lower ATP concentrations. Despite this, all three complexes were activated, due to increased Thr172 phosphorylation, when cells were incubated with mitochondrial inhibitors that increase cellular AMP. With g1 complexes, activation and Thr172 phosphorylation induced by the upstream kinase LKB1 (but not CaMKKb) in cell-free assays was markedly promoted by AMP and, to a smaller extent and less potently, by ADP. However, effects of AMP or ADP on activation and phosphorylation of the g2 and g3 complexes were small or insignificant. Binding of AMP or ADP protected all three g subunit complexes against inactivation by Thr172 dephosphorylation; with g2 complexes, ADP had similar potency to AMP, but with g1 and g3 complexes ADP was less potent than AMP. Thus, AMPK complexes containing different g subunit isoforms respond differently to changes in AMP, ADP or ATP. These differences may tune the responses of the isoforms to fit their differing physiological roles.