[Regulation of energy metabolism by AMPK: a novel therapeutic approach for the treatment of metabolic and cardiovascular diseases].
The 5' AMP-activated protein kinase (AMPK) is a sensor of cellular energy homeostasis well conserved in all eukaryotic cells. AMPK is activated by rising AMP and falling ATP, either by inhibiting ATP production or by accelerating ATP consumption, by a complex mechanism that results in an ultrasensitive response. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta. Once activated, it switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis) both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Dominant mutations in the regulatory gamma subunit isoforms cause hypertrophy of cardiac and skeletal muscle providing a link in human diseases caused by defects in energy metabolism. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of adipokines such as leptin and adiponectin. Moreover, the AMPK system is one of the probable target for the anti-diabetic drug metformin and rosiglitazone. The relationship between AMPK activation and beneficial metabolic effects provides the rationale for the development of new therapeutic strategies. Thus, pharmacological AMPK activation may, through signaling, metabolic and gene expression effects, reduce the risk of Type 2 diabetes, metabolic syndrome and cardiac diseases.
Foretz
Marc
M
Inserm U567, CNRS URM8104, Université Paris5, Institut Cochin, Département Endocrinologie, Métabolisme et Cancer, 24, rue du Faubourg Saint-Jacques, 75014 Paris, France.
Taleux
Nellie
N
Guigas
Bruno
B
Horman
Sandrine
S
Beauloye
Christophe
C
Andreelli
Fabrizio
F
Bertrand
Luc
L
Viollet
Benoît
B
D055372:AMP-Activated Protein Kinases; D000249:Adenosine Monophosphate / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000494:Allosteric Regulation; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000201:enzymology; D002784:Cholesterol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology; D015195:Drug Design; D002149:Energy Intake; D004734:Energy Metabolism / Q000502:physiology*; D004789:Enzyme Activation; D005227:Fatty Acids / Q000096:biosynthesis / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007031:Hypothalamus / Q000502:physiology; D050155:Lipogenesis / Q000187:drug effects / Q000502:physiology*; D008322:Mammals / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use
D005227:Fatty Acids; D009097:Multienzyme Complexes; D021122:Protein Subunits; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D008687:Metformin; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose