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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 124

Module 2: Figure AMPK control of metabolism
Adiponectin Glucagon
Ca 2+
Glucose
AdipoR
Glut4
2+ 1 Cyclic AMP
Ca 2
+ LKB1 AMP G-6-P
Glycogen E x o o t y c s i s
CaMKK + PKA
Ac + _
PGC-1 + 9
P
AMPK +
Ac P + Glucose
PGC-1
+
3
+ Gluconeogenesis
SIRT1 NAD + 6 G-6-P
GCN5 + +
P F K 2 -
+ 8
PGC-1 TORC P Acetyl-CoA F-6-P
P - 6 , 2 - F P a s e
ACC P 2 X
TORC X MDC F-2,6-P 2 PFK-1
5
X Malonyl-CoA + F-1,6-P 2 ase
Gluconeogenesis _
4 _
Mitochondrial F-1,6-P 2 Glycolysis
biogenesis FFA
FFA CPT1 oxidation
Lipogenic and 7
glycolytic genes
Mitochondrion Pyruvate
The pleiotropic action of AMP-activated protein kinase (AMPK) on cell metabolism.
An increase in the level of AMP during metabolic stress activates AMP-activated protein kinase (AMPK), which then has a number of actions, as
outlined in the text.
6. Lipid metabolism is strongly influenced by AMPK, this by exerting rapid effects on processes such as gluc-
which acts to divert fatty acids away from lipid syn- ose entry and glycolysis, as well as longer-term effects,
thesis and directs them towards the mitochondrial oxid- by regulating the transcription of genes for mitochondrial
ative pathway to produce ATP. The AMPK-dependent biogensis and glycolytic and lipogenic hormones (Module
phosphorylation of acetyl-CoA carboxylase (ACC) re- 2: Figure AMPK control of metabolism). The AMPK sig-
duces the conversion of acetyl-CoA into malonyl-CoA. nalling pathway functions in many different cell types:
7. The fall in malonyl-CoA levels has two import con- • In liver cells, AMPK inhibits gluconeogensis by redu-
sequences. First, fatty acid synthesis is reduced because cing the activity of PGC-1α (Module 7: Figure liver cell
malonyl-CoA is an important precursor for lipid syn- signalling)
thesis. Secondly, there is an increase in mitochondrial • AMPK regulates insulin biosynthesis in insulin-
ATP formation because malonyl-CoA normally inhib- secreting β1 cells (Module 7: Figure β-cell signalling)
its fatty acid oxidation.
• O 2 -sensing by the glomus cells in the carotid body
8. AMPK can influence the balance between glycolysis
(Module 10: Figure carotid body chemoreception)
and gluconeogenesis by stimulating the formation of
• Control of Glut4 insertion during excitation--
fructose 2,6-bisphosphate (F-2,6-P 2 ), which is a po-
metabolism coupling in skeletal muscle (see step 10 in
tent regulator of glycolysis through its ability to activ-
Module 7: Figure skeletal muscle E-C coupling)
ate 6-phosphofructo-1-kinase (PFK-1) and to inhibit
• AMPK plays an important role in cell growth control
fructose-1,6-bisphosphate 1-phosphatase. The forma-
by reducing protein synthesis when energy levels are
tion of F-2,6-P 2 is regulated by two separate signalling
low by acting through TOR (Module 9: Figure target of
pathways. AMPK promotes glycolysis by stimulat-
rapamycin signalling).
ing the phosphofructokinase (PFK-2) of the bifunc-
• The AMP signalling pathway plays an important role
tional enzyme, which has both kinase and phosphatase
in the control of autophagy (Module 11: Figure auto-
activities. Cyclic AMP acting through the fructose-
phagy).
2,6-bisphosphate 2-phosphatase component lowers the
level of F-2,6-P 2 , which reduces glycolysis and pro- The fact that AMPK plays such a central role in regu-
motes gluconeogenesis. lating energy metabolism has important implications for
9. AMPK stimulates the translocation of the glucose diabetes.
transporter (GLUT4) to the plasma membrane, where Glycogen storage disease in humans is caused by a muta-
it facilitates the entry of glucose in skeletal muscle and tion of the AMPK γ3-subunit.
heart cells.
LKB1
In summary, AMPK switches the cell away from energy- LKB1 is a serine/threonine protein kinase that functions
requiring processes towards energy conservation. It does to activate AMP-activated protein kinase (AMPK) by

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