AMP-activated protein kinase in metabolic control and insulin signaling

TY - JOUR

T1 - AMP-activated protein kinase in metabolic control and insulin signaling

AU - Towler, Mhairi C.

AU - Hardie, D. Grahame

PY - 2007/2/16

Y1 - 2007/2/16

N2 - The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca2+-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKß. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the a subunit being catalytic, the ß subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.

AB - The AMP-activated protein kinase (AMPK) system acts as a sensor of cellular energy status that is conserved in all eukaryotic cells. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). Activation in response to increases in AMP involves phosphorylation by an upstream kinase, the tumor suppressor LKB1. In certain cells (eg, neurones, endothelial cells, and lymphocytes), AMPK can also be activated by a Ca2+-dependent and AMP-independent process involving phosphorylation by an alternate upstream kinase, CaMKKß. Once activated, AMPK switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes such as biosynthesis and cell growth and proliferation. The AMPK complex contains 3 subunits, with the a subunit being catalytic, the ß subunit containing a glycogen-sensing domain, and the gamma subunits containing 2 regulatory sites that bind the activating and inhibitory nucleotides AMP and ATP. Although it may have evolved to respond to metabolic stress at the cellular level, hormones and cytokines such as insulin, leptin, and adiponectin can interact with the system, and it now appears to play a key role in maintaining energy balance at the whole body level. The AMPK system may be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin. It is a key player in the development of new treatments for obesity, type 2 diabetes, and the metabolic syndrome.

KW - AMP-Activated Protein Kinases

KW - Adenosine Monophosphate

KW - Adenosine Triphosphate

KW - Adipocytes

KW - Amino Acid Sequence

KW - Aminoimidazole Carboxamide

KW - Animals

KW - Binding Sites

KW - Calcium

KW - Calcium-Calmodulin-Dependent Protein Kinase Kinase

KW - Carbohydrate Metabolism

KW - Cell Cycle

KW - Consensus Sequence

KW - Diabetes Mellitus

KW - Energy Metabolism

KW - Enzyme Activation

KW - Hepatocytes

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin

KW - Lipid Metabolism

KW - Metformin

KW - Mice

KW - Mice, Knockout

KW - Models, Molecular

KW - Molecular Sequence Data

KW - Multienzyme Complexes

KW - Muscle Cells

KW - Neoplasms

KW - Obesity

KW - Oxygen Consumption

KW - Peptide Hormones

KW - Phosphorylation

KW - Protein Processing, Post-Translational

KW - Protein Subunits

KW - Protein-Serine-Threonine Kinases

KW - Rats

KW - Ribonucleotides

KW - Sequence Alignment

KW - Sequence Homology, Amino Acid

U2 - 10.1161/01.RES.0000256090.42690.05

DO - 10.1161/01.RES.0000256090.42690.05

M3 - Article

C2 - 17307971

SN - 0009-7330

VL - 100

SP - 328

EP - 341

JO - Circulation Research

JF - Circulation Research

IS - 3

ER -