AMP-Activated Protein Kinase – Development of the Energy Sensor Concept

Hardie, D. Grahame; Hawley, Simon A.; Scott, John W.

doi:10.1113/jphysiol.2006.108944

Cited by 813Metabolism, Diabetes, and CancerBiochemical and Molecular ResearchPeroxisome Proliferator-Activated Receptors

AMP-Activated Protein Kinase – Development of the Energy Sensor Concept

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Hardie, D. Grahame, Hawley, Simon A., Scott, John W.·2006·The Journal of Physiology

DOI 10.1113/jphysiol.2006.108944PMC PMC1817788

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Abstract

The LKB1-->AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory gamma subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.

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AMPK functions as an energy sensor that coordinates multiple protective and energy-conserving signaling pathways including the pathways activated by caloric restriction.
“AMPK functions as an energy sensor that coordinates multiple protective and energy-conserving signaling pathways including the pathways activated by caloric restriction and referred to as the fuel gauge of the cell by serving as an energy sensor (100, 101) (Figure 1).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [101]

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Authors: Hardie, D. G., Hawley, S. A., & Scott, J. W.
Affiliations: University of Dundee (GB)
Corresponding author: Hardie, D. Grahame
ORCID: Hardie, D. Grahame
Scott, John W.
Venue: The Journal of Physiology
Publisher: Wiley
Published: 2006-06-19
Volume: 574
Issue: 1
Pages: 7-15
ISSN: 0022-3751 (ISSN-L)
1469-7793
DOI: 10.1113/jphysiol.2006.108944
PMC: PMC1817788
OpenAlex: W2170716497
Cited by: 813
References: 88
Citations by year: 2026: 4 · 2025: 18 · 2024: 15 · 2023: 14 · 2022: 20 · 2021: 29 · 2020: 29 · 2019: 20 · 2018: 44 · 2017: 27 · 2016: 34 · 2015: 41 · 2014: 41 · 2013: 43 · 2012: 68
FWCI: 5.78
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The Journal of Physiology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
European Commission (LSHMCT-2004-005272)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: AMPK, LKB1, energy sensing, AMP/ATP ratio, metabolic stress, leptin, adiponectin, obesity, type 2 diabetes, metformin
MeSH terms: Animals, Diabetes Mellitus, Energy Metabolism, Humans, Multienzyme Complexes, Myocardium, Obesity, Oxygen, Protein Serine-Threonine Kinases, Oxidative Stress, Muscle, Skeletal, Metabolic Syndrome, AMP-Activated Protein Kinases

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AMP-Activated Protein Kinase – Development of the Energy Sensor Concept

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