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REVIEW
AMPK: a key regulator of energy balance in the single
cell and the whole organism
DG Hardie
Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, UK
The AMP-activated protein kinase (AMPK) system is a key player in regulating energy balance at both the cellular and whole-body
levels, placing it at centre stage in studies of obesity, diabetes and the metabolic syndrome. It is switched on in response to metabolic
stresses such as muscle contraction or hypoxia, and modulated by hormones and cytokines affecting whole-body energy balance
such as leptin, adiponectin, resistin, ghrelin and cannabinoids. Once activated, it switches on catabolic pathways that generate
adenosine triphosphate (ATP), while switching off ATP-consuming anabolic processes. AMPK exists as heterotrimeric complexes
comprising a catalytic a-subunit and regulatory b-andg-subunits. Binding of AMP to the g-subunit, which is antagonized by high
ATP, causes activation of the kinase by promoting phosphorylation at threonine (Thr-172) on the a-subunit by the upstream kinase
LKB1, allowing the system to act as a sensor of cellular energy status. In certain cells, AMPK is activated in response to elevation of
cytosolic Ca
2þ
via phosphorylation of Thr-172 by calmodulin-dependent kinase kinase-b(CaMKKb). Activation of AMPK, either in
response to exercise or to pharmacological agents, has considerable potential to reverse the metabolic abnormalities associated with
type 2 diabetes and the metabolic syndrome. Two existing classes of antidiabetic drugs, that is, biguanides (for example, metformin)
and the thiazolidinediones (for example, rosiglitazone), both act (at least in part) by activation of AMPK. Novel drugs activating AMPK
may also have potential for the treatment of obesity.
International Journal of Obesity (2008) 32, S7–S12; doi:10.1038/ijo.2008.116
Keywords: diabetes; metabolic syndrome; LKB1; calmodulin-dependent kinase kinase
Introduction
The AMP-activated protein kinase (AMPK) system was
discovered in mammalian cell extracts as activities that
phosphorylated and inactivated key enzymes of lipid biosynth-
esis, that is, acetyl-CoA carboxylase and 3-hydroxy-3-
methylglutaryl-CoA reductase, which regulate fatty acid and
cholesterol synthesis, respectively.
1
In 1987 the author’s
laboratory showed that these activities, which had been
presumed to be distinct, were in fact functions of the same
protein kinase. This kinase was allosterically activated by
50-AMP and was also activated by phosphorylation by upstream
kinases, and was renamed AMPK in 1988.
1
Structure and regulation of AMPK
AMP-activated protein kinase and its orthologues in lower
eukaryotes, for example, budding yeast, are now known to
exist as heterotrimeric complexes consisting of catalytic
a-subunits and regulatory b- and g-subunits. Humans and
rodents express two isoforms of aand b(a1, a2; b1, b2), and
three isoforms of g(g1, g2 and g3) encoded by distinct
genes.
2
Some of these are also subject to alternative splicing,
leading to a large and diverse array of heterotrimeric
complexes. The a-subunits have conventional serine/threo-
nine kinase domains at the N-terminus, containing a
conserved threonine residue (Thr-172) whose phosphoryla-
tion by upstream kinases is absolutely required for their
activity. The primary upstream kinase was recently identified
to be a complex between the tumour suppressor, LKB1, and
two accessory subunits, STRAD (STE-20 related adaptor
protein) and MO25.
3,4
These findings were exciting, because
LKB1 was originally identified as the gene mutated in Peutz–
Jeghers syndrome, an inherited predisposition to cancer in
humans. LKB1 is a classical tumour suppressor: subjects with
this syndrome have heterozygous loss-of-function mutations
in the LKB1 gene and develop numerous polyps (benign
tumours) in the intestine, probably due to loss of expression
of their functional gene copy. They also have a 15-fold
increased risk of developing malignant tumors at other
sites.
5
LKB1 is now known to act upstream of 12 other
members of the AMPK-related kinase family, in addition to
Correspondence: Dr DG Hardie, Division of Molecular Physiology, College of
Life Sciences, University of Dundee, Sir James Black Centre, Dow Street,
Dundee DD1 5EH, UK.
E-mail: d.g.hardie@dundee.ac.uk
International Journal of Obesity (2008) 32, S7 –S12
&
2008 Macmillan Publishers Limited All rights reserved 0307-0565/08
$
30.00
www.nature.com/ijo
the two isoforms of the AMPK catalytic subunit (a1 and a2).
5
There is evidence (discussed further below) that activation of
AMPK inhibits cell growth and proliferation. This makes it
likely that the ability of LKB1 to activate AMPK explains
much of its tumour suppressor effect, although a role for the
alternate downstream kinases cannot be discounted at
present.
The LKB1 complex appears to be constitutively active and
is not regulated by AMP. Binding of AMP to AMPK promotes
net phosphorylation of Thr-172 by inhibiting its depho-
sphorylation (by making the kinase a less efficient substrate
for protein phosphatases), as well as allosterically activating
the phosphorylated form of the kinase. These two effects of
AMP effectively multiply together, so that a small increase in
AMP can produce a much larger effect on the kinase
activity.
6
Both effects are also antagonized by high concen-
trations of ATP, so that AMPK is activated in a sensitive
manner by a small rise in the AMP/ATP ratio. If the adenylate
kinase reaction is at equilibrium (as appears to be the case in
most mammalian cells), the AMP/ATP ratio will vary as the
square of the ADP/ATP ratio, making the former ratio a very
sensitive indicator of cellular energy status.
Some cells express an alternate pathway for AMPK
activation that is triggered by increases in cytoplasmic
Ca
2þ
, leading to activation of calmodulin-dependent kinase
kinase-b(CaMKKb) which, like LKB1, can phosphorylate
Thr-172 on the AMPK a-subunit.
7–9
However, unlike the
effect of LKB1, phosphorylation by CaMKKbappears to be
AMP-independent. The tissue distribution of CaMKKbis
more restricted than that of LKB1, with the former being
most abundant in neurones and cells of the endothelial/
haemopoietic lineage.
The AMPK b-subunits have two conserved regions, a
central glycogen-binding domain and a C-terminal domain
required for forming a complex with the a- and g-subunits.
10
The glycogen-binding domain causes the complex to
partially associate with glycogen particles. The function of
this interaction is not known, although glycogen synthase
(another component of glycogen particles) is a downstream
target that is known to be phosphorylated and inactivated by
AMPK.
11
One interesting possibility is that the AMPK system
can sense some aspect of glycogen structure and provide a
feedback regulation on glycogen synthesis. The g-subunits
contain four tandem repeats of a structure known as a
cystathionine-b-synthase motif: these are now known to act
in pairs to form two modules (termed Bateman domains)
each of which binds one molecule of AMP or ATP in a
mutually exclusive manner.
12
Bateman domains also occur
in a few other proteins, where they bind adenosine-contain-
ing ligands, such as AMP, ATP or S-adenosyl methionine.
12
Intriguingly, mutations in these domains lead to a variety of
human hereditary diseases that are all caused by defective
ligand binding. In the case of AMPK these mutations, which
cause heart disease of varying severity associated with
excessive glycogen storage, prevent both binding of AMP
and allosteric activation, proving that the Bateman domains
on the g-subunit form the regulatory binding sites for AMP
and ATP.
12,13
Activation of AMPK by metabolic stress
As the LKB1-AMPK signalling pathway is activated by
elevation of the AMP/ATP ratio, it is switched on by any
metabolic stress that disturbs energy balance by interfering
with ATP synthesis, such as glucose deprivation, hypoxia or
ischaemia, or metabolic poisons that inhibit glycolysis (for
example, 2-deoxyglucose), the tricarboxylic acid cycle (for
example, arsenite) or oxidative phosphorylation (for exam-
ple, oligomycin, antimycin A, rotenone).
2
With most
mammalian cells, glucose deprivation is unlikely to be a
major issue in vivo, because they express isoforms of glucose
transporter and hexokinase that are saturated by low
concentrations of glucose, such that inhibition of ATP
synthesis and activation of AMPK would only occur when
plasma glucose dropped to levels incompatible with life.
However, specialized glucose-sensing cells such as the b-cells
in the Islets of Langerhans in the pancreas, and glucose-
regulated neurones in the hypothalamus, express isoforms of
glucose transporter (GLUT2) and hexokinase (hexokinase IV,
also known as glucokinase) with a much higher K
m
for
glucose, so that AMPK in these cells is activated by decreases
in blood glucose within the more normal physiological
range. Thus, in cell lines derived from rodent pancreatic b-
cells, AMPK is activated by low glucose and inhibited by high
glucose
14
whereas, in fasted mice, intracerebroventricular
injection of glucose, or refeeding, inhibits the a2-isoform of
AMPK in regions of the hypothalamus.
15
Moreover, the
known downstream consequences of lowering external
glucose in both cell types, that is, decreased insulin secretion
(b-cells) or increased feeding behaviour (hypothalamus) can
be mimicked by the activation of AMPK at these sites, either
by pharmacological or molecular biological interventions.
14–16
Thus, the AMPK system is a key player in the regulation of
energy balance at the whole-body level, not just at the
cellular level.
Just as there are specialized glucose-sensing cells in the
pancreas and hypothalamus, so there are specialized oxygen-
sensing cells where AMPK is regulated by normal physiolo-
gical variations in oxygen tension. These include the glomus
cells in the carotid body, which sense hypoxia in blood
supplied to the brain and regulate breathing, and pulmonary
artery smooth muscle cells, which contract in response to
hypoxia (unlike most arterial smooth muscle cells, which
relax), thus diverting blood flow away from poorly oxyge-
nated regions of the lung. In collaboration with the
laboratories of Evans and Peers,
17
the author has recently
shown that activation of AMPK mimics the effects of
hypoxia in these cells: (i) in glomus cells, entry of
extracellular Ca
2þ
via voltage-gated Ca
2þ
channels and
firing of action potentials in afferent neurones leading to the
brain; and (ii) in pulmonary artery smooth muscle, release of
AMPK and energy balance
DG Hardie
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International Journal of Obesity
Ca
2þ
from the endoplasmic reticulum and consequent
contraction.
All of the metabolic stresses mentioned above increase
cellular AMP/ATP by inhibiting ATP production. A stress that
activates AMPK by increasing ATP consumption is contrac-
tion in skeletal muscle.
18
There is now good evidence that
many of the acute metabolic responses to exercise, including
increased glucose uptake and fatty acid oxidation,
19,20
as
well as the long-term adaptations to regular endurance
exercise, such as increased expression of the glucose
transporter GLUT4
21
and increased mitochondrial biogen-
esis,
22
are at least partly mediated by AMPK activation.
Regulation of AMPK by hormones and cytokines
Although orthologues of AMPK are present in primitive
single-celled eukaryotes, suggesting that the system existed
prior to the evolution of hormones and cytokines, the latter
nevertheless appear to have acquired the ability to regulate
the AMPK system. In particular, AMPK is modulated by
cytokines released by adipocytes (termed adipokines) that
regulate whole-body energy balance, such as leptin, adipo-
nectin and resistin (reviewed in Kahn et al.
2
). Leptin and
adiponectin both activate AMPK and increase glucose uptake
and fatty acid oxidation in skeletal muscle, thus stimulating
whole-body energy expenditure. Adiponectin also activates
AMPK in liver, stimulating fatty acid oxidation and inhibit-
ing glucose production, whereas resistin appears to have the
opposite effects. Remarkably, although leptin activates
AMPK in skeletal muscle, it causes inhibition of the a2-
isoform of the kinase in regions of the hypothalamus in
fasted mice, concomitant with repression of food intake.
Other anorexigenic agents, such as insulin, melanocortin
receptor agonists and high glucose, also inhibit AMPK in the
hypothalamus of fasted mice, whereas orexigenic agents
such as agouti-related protein, the gut hormone ghrelin, and
cannabinoids activate the kinase in the hypothalamus of fed
mice.
2,23
In addition, artificially increasing AMPK activity in
the hypothalamus by using drugs or by expressing activated
mutants stimulates food intake even in the fed state.
2
Taken
together, these findings suggest that AMPK, acting both in
the hypothalamus and in the periphery, is a key player in the
regulation of the balance between whole-body energy intake
and energy expenditure, and hence in the development of
obesity.
The mechanisms by which adipokines and other agents
affecting food intake modulate AMPK activity remain
unclear. However, in cells of the endothelial/haematopoietic
lineage the Ca
2þ
-CaMKK pathway (discussed above)
switches on AMPK in response to activation of certain
receptors. In human umbilical vein endothelial cells,
thrombin increases cytoplasmic Ca
2þ
via receptor-mediated
release of inositol-1,4,5-trisphosphate and consequent re-
lease of Ca
2þ
from the endoplasmic reticulum. This activates
AMPK, an effect that is reduced by the inhibition of CaMKKb
by pharmacological means or by interfering RNA ap-
proaches.
24
AMPK is also activated by stimulation of the
antigen receptor in T lymphocytes, an effect that can be
mimicked by Ca
2þ
ionophores and is blocked by pharma-
cological inhibitors of CaMKK.
25
The function of AMPK
activation under these circumstances is not clear, but one
can speculate that the Ca
2þ
trigger represents a feed-forward
signal that anticipates the large demand for ATP that often
follows an increase in cytoplasmic Ca
2þ
(for example, the
rapid growth and proliferation that follows activation of T
lymphocytes).
Downstream targets of AMPK
A full discussion of this topic is beyond the scope of this brief
review, and the reader is referred elsewhere for detailed
discussion.
2
In general (as summarized in Figure 1), AMPK
switches on catabolic processes that provide alternative
routes to generate ATP (for example, glucose uptake,
glycolysis, fatty acid oxidation and mitochondrial biogen-
esis), while switching off anabolic processes that consume
ATP, such as the synthesis of fatty acids, triglyceride,
cholesterol, glucose (via gluconeogenesis) and glycogen.
These effects can occur through distinct mechanisms with
different time courses: (i) acute effects on metabolism due to
direct phosphorylation of metabolic enzymes (for example,
inhibition of cholesterol synthesis due to phosphorylation of
3-hydroxy-3-methylglutaryl-CoA reductase); (ii) longer-term
effects due to changes in gene expression (for example,
upregulation of glucose and fat oxidation due to increased
expression of mitochondrial genes, downregulation of
gluconeogenic genes); and (iii) combined acute and longer-
term effects (for example, inhibition of fatty acid synthesis
via direct phosphorylation of the ACC1 isoform of acetyl-
CoA carboxylase, combined with inhibition of expression of
the ACC1 and fatty acid synthase genes). Although not
shown in Figure 1, AMPK activation also inhibits protein
synthesis, both via inhibition of the target-of-rapamycin
pathway
26
(thus inhibiting initiation of translation), and via
activation of elongation factor-2 kinase
27
(thus inhibiting
elongation of translation). The ability of AMPK to inhibit
protein synthesis and other biosynthetic pathways contri-
butes to its effects to limit hypertrophy of non-dividing cells,
whereas in proliferating cells, progress through the cell cycle
is also blocked by AMPK activation.
28
Role of AMPK in obesity, diabetes and the
metabolic syndrome
The ability of AMPK to switch cells from an anabolic to a
catabolic state suggests that activators of the kinase might be
effective agents for treatment of obesity, type 2 diabetes and
the metabolic syndrome. Type 2 diabetes is characterized by
an elevated plasma glucose primarily caused by insulin
AMPK and energy balance
DG Hardie
S9
International Journal of Obesity
resistance, and risk of developing this condition is greatly
increased by obesity. Activation of AMPK has the potential to
lower plasma glucose both by repressing expression of
enzymes of gluconeogenesis in the liver, and by increasing
glucose uptake by muscle and other tissues (Figure 1). Insulin
resistance is also often associated with elevated storage of
triglycerides in tissues other than adipose tissue such as
muscle and liver, together with a relative deficit in
mitochondrial oxidative capacity in those organs.
29
By
inhibiting fatty acid and triglyceride synthesis and stimulat-
ing fatty acid oxidation and mitochondrial biogenesis,
AMPK activation has the potential to reduce hypertriglycer-
idemia, as well as elevated storage of triglycerides in muscle
and liver. Finally, the metabolic syndrome involves a cluster
of related metabolic abnormalities that are all potentially
reversed by AMPK activation, including insulin resistance,
abdominal obesity, hypertension, and altered plasma lipids,
especially hypertriglyceridemia and low high-density lipo-
protein cholesterol. These abnormalities are all risk factors
for cardiovascular disease.
The developing epidemic of obesity and type 2 diabetes in
developed and developing countries is generally thought to
be due to increasing urbanization, with consequent de-
creased levels of exercise in the general population, coupled
with all-day and all-year availability of high-energy food-
stuffs. It is well established that regular exercise is an
effective method of treating insulin resistance and type 2
diabetes, as well as preventing their onset in susceptible
individuals, and it seems likely that the beneficial effects of
exercise are at least partly mediated by AMPK activation. The
ability to more directly test the efficacy of AMPK activation
came with the development of 5-aminoimidazole-4-carbox-
amide ribonucleoside (which is taken up into cells and
converted to the AMP mimetic ZMP) as a method to activate
AMPK in intact cells. In vivo treatment with 5-aminoimida-
zole-4-carboxamide ribonucleoside of several animal models
of insulin resistance and the metabolic syndrome, such as
genetically obese (ob/ob or fa/fa) mice and rats, and fat-fed
rats, showed that the drug was able to reverse glucose
intolerance and insulin resistance, lower plasma triglycerides
and free fatty acids, increase high-density lipoprotein
cholesterol, and even reduce hypertension (see Hardie
(2004)
30
). Further proof of the concept that AMPK activators
had potential for treatment of insulin resistance and type 2
diabetes came with findings that two existing classes of drug
used to treat these conditions, that is, the biguanides (for
example, metformin) and the thiazolidinediones (for exam-
ple, rosiglitazone) can both activate AMPK.
31,32
Both classes
of drug may activate AMPK in part by inhibiting Complex I
of the respiratory chain
33
and thus elevating cellular AMP/
ATP ratios. The thiazolidinediones are also agonists for
peroxisome proliferator-activated receptor-g(PPAR-g)in
adipocytes,
34
through which they are known to increase
the expression and release of adiponectin.
35
Release of
adiponectin explains, at least in part, the therapeutic actions
of thiazolidinediones,
36
although the downstream effects of
adiponectin are, of course, also thought to be mediated by
AMPK. In the case of metformin, there is now good evidence
fatty acid
CO2
glucose
pyruvate
glycogen
triglyceride
glucose
fatty acid fatty acid
glucose
glucose fatty acid
pyruvate CO2
SKELETAL MUSCLE
LIVER
ADIPOSE
TISSUE
Stimulated by AMPK:
Inhibited by AMPK:
acetyl
-CoA
cholesterol
glucose
fatty acid
pyruvate
CO2
glycogen
triglyceride
HEART
Figure 1 Summary of the acute and longer-term changes in carbohydrate and lipid metabolism induced by AMPK activation in the liver, heart, skeletal muscle and
adipose tissue of mammals. Processes stimulated by AMPK activation are shown with thick arrows, those inhibited by AMPK activation are shown by thin arrows with
bars across.
AMPK and energy balance
DG Hardie
S10
International Journal of Obesity
that activation of liver AMPK mediates its antihyperglycemic
effects, because they are completely ablated in a mouse with
a liver-specific knockout of the upstream kinase, LKB1, in
which AMPK can no longer be activated by the drug.
37
It remains unclear at present whether activators of AMPK
would be effective treatments for obesity per se. However,
encouraging pointers in that direction are findings that three
mouse strains that are resistant to diet-induced obesity, that
is: (i) stearoyl-CoA desaturase-1 knockouts;
38
(ii) mice
overexpressing uncoupling protein-1 in white adipocytes;
39
and (iii) mice overexpressing uncoupling protein-3 in
skeletal muscle,
40
all exhibit increased basal activity of
AMPK in the tissues affected.
Conclusions
The AMPK system is switched on either by LKB1, triggered by
increases in cellular AMP/ATP ratio or (in specific cell types)
by elevated Ca
2þ
and CaMKKb. Whatever the upstream
trigger(s), AMPK activation causes a switch from an anabolic
state promoting increased synthesis and storage of glucose,
glycogen, fatty acids, cholesterol and triglycerides, together
with increased cell growth (that is, hypertrophy) and/or
proliferation, to a catabolic state involving oxidation of
glucose, fatty acids and triglycerides, and inhibition of cell
growth and proliferation. Activation of AMPK, either by
increased levels of exercise or by pharmacological means, has
great potential to reverse the metabolic abnormalities of type
2 diabetes and the metabolic syndrome, and perhaps also
obesity.
Acknowledgements
Recent studies in the author’s laboratory have been funded
by Programme Grants from the Wellcome Trust, and by the
EXGENESIS Integrated project (LSHM-CT-2004-005272)
funded by the European Commission.
Conflict of interest
The author states no conflict of interest.
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