AMPK activators: mechanisms of action and physiological activities

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Abstract

AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases. In this review, we provide a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK. We discuss the functional differences among isoform-specific AMPK complexes and their significance regarding the development of novel AMPK activators and the potential for combining different AMPK activators in the treatment of human disease.

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AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

Joungmok Kim, Mondira Kundu, Benoit Viollet … (2011)

Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

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AMPK: a nutrient and energy sensor that maintains energy homeostasis.

D Hardie, Fiona Ross, Simon A. Hawley (2012)

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.

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AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

Russell G. Jones, David Plas, Sara Kubek … (2005)

Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Mol Med

Journal ID (iso-abbrev): Exp. Mol. Med

Title: Experimental & Molecular Medicine

Publisher: Nature Publishing Group

ISSN (Print): 1226-3613

ISSN (Electronic): 2092-6413

Publication date (Print): April 2016

Publication date (Electronic): 01 April 2016

Publication date PMC-release: 1 April 2016

Volume: 48

Issue: 4

Page: e224

Affiliations

[1 ]Depatment of Oral Biochemistry and Molecular Biology, School of Dentistry, Kyung Hee University , Seoul, Korea

[2 ]Department of Biomedical Science, Graduate School, Kyung Hee University , Seoul, Korea

[3 ]Department of Biochemistry and Molecular Biology, Graduate School, Kyung Hee University , Seoul, Korea

Author notes

[* ]Department of Biochemistry and Molecular Biology, Graduate School, Kyung Hee University , 26, Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. E-mail: hajh@ 123456khu.ac.kr

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Publisher Item ID: emm201616

DOI: 10.1038/emm.2016.16

PMC ID: 4855276

PubMed ID: 27034026

SO-VID: 68e81463-c5f6-47fb-95c6-132c57b47213

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

AMPK activators: mechanisms of action and physiological activities

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Most cited references 128

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.

AMPK: a nutrient and energy sensor that maintains energy homeostasis.

AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

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