AMPK: positive and negative regulation, and its role in whole-body energy homeostasis
Introduction
The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, expressed in essentially all eukaryotic cells as heterotrimeric complexes containing catalytic α subunits and regulatory β and γ subunits. In mammals, AMPK is activated by increases in AMP:ATP or ADP:ATP ratios, which occur when cellular energy status has been compromised. Activation occurs in response to metabolic stresses that either interfere with ATP production or that accelerate ATP consumption, when AMPK acts to restore energy homeostasis by activating alternate catabolic processes generating ATP, while inhibiting ATP-requiring processes [1, 2]. Because of the reversible reaction catalyzed by adenylate kinase (2ADP ↔ ATP + AMP), increases in AMP in stressed cells are always much larger than increases in ADP or decreases in ATP [3], so it makes sense for AMP to be the primary signal to which the system responds. This review will focus on mechanisms of positive and negative regulation of AMPK, and its role in whole body energy homeostasis; readers more interested in its downstream targets within the cell should consult other reviews [1, 2].
Section snippets
Regulation of AMPK by nucleotides, pharmacological agents and Ca2+
As its name suggests, AMPK is allosterically activated by AMP. The physiological importance of this mechanism has been questioned [4], but studies of cells expressing only a mutant AMPK that cannot be regulated by the alternate phosphorylation mechanism suggest that the allosteric effect is a key component of the overall activation mechanism [3]. AMPK is also activated by other allosteric effectors (A-769662, 991, MT 63-78; Figure 1, top), all synthetic compounds derived from high-throughput
AMPK may be activated by LKB1 at the surface of the lysosome
Recombinant LKB1 complexes phosphorylate and activate purified AMPK in reconstituted cell-free assays, with no other components apparently necessary [3]. Nevertheless, two remarkable recent papers [21••, 22•] suggest that the interaction between LKB1 and AMPK within cells may be facilitated by interactions with adapter proteins that recruit both complexes to the two-dimensional surface of the lysosome. Initial clues came from studies of axin, a scaffold protein originally identified as a
AMPK regulates whole-body as well as cellular energy balance
AMPK orthologs are clearly present in unicellular eukaryotes, suggesting that the system originally evolved to regulate energy homeostasis in a cell-autonomous manner. However, in multicellular organisms hormones that regulate whole-body energy balance, particularly through effects on the hypothalamus, appear to have adapted to interact with AMPK (Figure 2). For example, the hormones ghrelin released from the stomach during fasting, and adiponectin released from adipocytes of lean individuals,
Structural analysis of the AMPK complex
Two key events during the last year were the publication of the first almost complete crystal structures for AMPK, of the human α2β1γ1 [6••] and α1β1γ1 [9•] complexes. Both had been phosphorylated on Thr172 and crystallized in the presence of AMP and either A-76692 or 991, so were in a fully activated state. The structures, which are broadly similar, can be divided into two distinct halves that I will term the catalytic and nucleotide-binding modules (Figure 3); these probably correspond to the
Negative regulation of AMPK by phosphorylation
The C-terminal domains of vertebrate α subunit isoforms contain the ‘ST loop’, a serine/threonine-rich insert of 50–60 amino acids not present in orthologs from most lower eukaryotes [46•]. In the two recent crystal structures the ST loop was either unresolved [6••] or had been replaced by a short artificial linker [9•]. The residues defining the ends of this loop are close to Thr172 (Figure 3, right), and the loop appears to contain several regulatory phosphorylation sites. For example, Ser485
Conclusions and perspectives
It is becoming clear that AMPK, a signaling protein that may have originally evolved to regulate energy balance in a cell-autonomous manner, has adapted in multicellular animals to regulate whole-body energy balance. It does this primarily by mediating effects of hormones that act in the hypothalamus to regulate energy intake (ghrelin, leptin, adiponectin) and/or energy expenditure (T3, GLP-1). Given this role, pharmacological activation of AMPK is an obvious target for treatment of metabolic
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Recent studies in the author's laboratory have been supported by a Senior Investigator Award from the Wellcome Trust [097726], a Programme Grant from Cancer Research UK (C37030/A15101), and the pharmaceutical companies supporting the Division of Signal Transduction Therapy at the University of Dundee (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck KgaA, Janssen Pharmaceutica and Pfizer).
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