The AMP-activated protein kinase: more than an energy sensor

2007 ◽  
Vol 43 ◽  
pp. 121-138 ◽  
Author(s):  
Louis Hue ◽  
Mark H. Rider
Keyword(s):  
Protein Kinase ◽  
Metabolic Diseases ◽  
Cellular Level ◽  
Whole Body ◽  
Energy Status ◽  
Cellular Energy ◽  
The Metabolic Syndrome ◽  
Control Food ◽  
Control Food Intake ◽  
Amp Activated Protein Kinase

The AMPK (AMP-activated protein kinase) is a highly conserved eukaryotic protein serine/threonine kinase. It mediates a nutrient signalling pathway that senses cellular energy status and was appropriately called the fuel gauge of the cell. At the cellular level, AMPK controls energy homoeostasis by switching on catabolic ATP-generating pathways, while switching off anabolic ATP-consuming processes. Its effect on energy balance extends to whole-body energy homoeostasis, because, in the hypothalamus, it integrates nutritional and hormonal signals that control food intake and body weight. The interest in AMPK also stems from the demonstration of its insulin-independent stimulation of glucose transport in skeletal muscle during exercise. Moreover, the potential importance of AMPK in metabolic diseases is supported by the notion that AMPK mediates the anti-diabetic action of biguanides and thiazolidinediones and that it might be involved in the metabolic syndrome. Finally, the more recent demonstration that AMPK activation could occur independently of changes in cellular energy status, suggests that AMPK action extends to the control of non-metabolic functions.

scholarly journals Energy sensing by the AMP-activated protein kinase and its effects on muscle metabolism

2010 ◽  
Vol 70 (1) ◽  
pp. 92-99 ◽  
Author(s):  
D. Grahame Hardie
Keyword(s):  
Protein Kinase ◽  
Endurance Exercise ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Whole Body ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Energy Status ◽  
Cellular Energy ◽  
Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status, and a regulator of energy balance at both the cellular and whole body levels. Although ubiquitously expressed, its function is best understood in skeletal muscle. AMPK contains sites that reversibly bind AMP or ATP, with an increase in cellular AMP:ATP ratio (signalling a fall in cellular energy status) switching on the kinase. In muscle, AMPK activation is therefore triggered by sustained contraction, and appears to be particularly important in the metabolic changes that occur in the transition from resistance to endurance exercise. Once activated, AMPK switches on catabolic processes that generate ATP, while switching off energy-requiring processes not essential in the short term. Thus, it acutely activates glucose uptake (by promoting translocation of the transporter GLUT4 to the membrane) and fatty acid oxidation, while switching off glycogen synthesis and protein synthesis (the later via inactivation of the mammalian target-of-rapamycin pathway). Prolonged AMPK activation also causes some of the chronic adaptations to endurance exercise, such as increased GLUT4 expression and mitochondrial biogenesis. AMPK contains a glycogen-binding domain that causes a sub-fraction to bind to the surface of the glycogen particle, and it can inhibit glycogen synthesis by phosphorylating glycogen synthase. We have shown that AMPK is inhibited by exposed non-reducing ends in glycogen. We are working on the hypothesis that this ensures that glycogen synthesis is rapidly activated when glycogen becomes depleted after exercise, but is switched off again as soon as glycogen stores are replenished.

Molecular Regulation of Energy Balance

2019 ◽  
Author(s):  
D. Grahame Hardie ◽  
A. Mark Evans
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Adenine Nucleotides ◽  
Kinase Domain ◽  
Cellular Level ◽  
Whole Body ◽  
Energy Status ◽  
Α Subunit ◽  
Cellular Energy ◽  
Synthetic Drugs

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that monitors the levels of AMP and ADP relative to ATP. If increases in AMP:ATP and/or ADP:ATP ratios are detected (indicating a reduction in cellular energy status), AMPK is activated by the canonical mechanism involving both allosteric activation and enhanced net phosphorylation at Thr172 on the catalytic subunit. Once activated, AMPK phosphorylates dozens of downstream targets, thus switching on catabolic pathways that generate ATP and switching off anabolic pathways and other energy-consuming processes. AMPK can also be activated by non-canonical mechanisms, triggered either by glucose starvation by a mechanism independent of changes in adenine nucleotides, or by increases in intracellular Ca2+ in response to hormones, mediated by the alternate upstream kinase CaMKK2. AMPK is expressed in almost all eukaryotic cells, including neurons, as heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits. The α subunits contain the kinase domain and regulatory regions that interact with the other two subunits. The β subunits contain a domain that, with the small lobe of the kinase domain on the α subunit, forms the “ADaM” site that binds synthetic drugs that are potent allosteric activators of AMPK, while the γ subunits contain the binding sites for the classical regulatory nucleotides, AMP, ADP, and ATP. Although much undoubtedly remains to be discovered about the roles of AMPK in the nervous system, emerging evidence has confirmed the proposal that, in addition to its universal functions in regulating energy balance at the cellular level, AMPK also has cell- and circuit-specific roles at the whole-body level, particularly in energy homeostasis. These roles are mediated by phosphorylation of neural-specific targets such as ion channels, distinct from the targets by which AMPK regulates general, cell-autonomous energy balance. Examples of these cell- and circuit-specific functions discussed in this review include roles in the hypothalamus in balancing energy intake (feeding) and energy expenditure (thermogenesis), and its role in the brainstem, where it supports the hypoxic ventilatory response (breathing), increasing the supply of oxygen to the tissues during systemic hypoxia.

scholarly journals AMPK: Regulating Energy Balance at the Cellular and Whole Body Levels

Physiology ◽  
2014 ◽  
Vol 29 (2) ◽  
pp. 99-107 ◽  
Author(s):  
D. Grahame Hardie ◽  
Michael L. J. Ashford
Keyword(s):  
Energy Balance ◽  
Protein Kinase ◽  
Energy Homeostasis ◽  
Adenine Nucleotide ◽  
Cellular Level ◽  
Whole Body ◽  
Balancing Energy ◽  
Body Level ◽  
Multicellular Organisms ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase appears to have evolved in single-celled eukaryotes as an adenine nucleotide sensor that maintains energy homeostasis at the cellular level. However, during evolution of more complex multicellular organisms, the system has adapted to interact with hormones so that it also plays a key role in balancing energy intake and expenditure at the whole body level.

scholarly journals Sumoylation of AMPKβ2 subunit enhances AMP-activated protein kinase activity

2013 ◽  
Vol 24 (11) ◽  
pp. 1801-1811 ◽  
Author(s):  
Teresa Rubio ◽  
Santiago Vernia ◽  
Pascual Sanz
Keyword(s):  
Protein Kinase ◽  
Kinase Activity ◽  
Catalytic Domain ◽  
Protein Kinase Activity ◽  
Energy Status ◽  
Regulatory Subunits ◽  
Cellular Energy ◽  
Sumo Ligase ◽  
Ampk Activity ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is a heterotrimer composed of a catalytic α and two regulatory subunits (β and γ). AMPK activity is regulated allosterically by AMP and by the phosphorylation of residue Thr-172 within the catalytic domain of the AMPKα subunit by upstream kinases. We present evidence that the AMPKβ2 subunit may be posttranslationally modified by sumoylation. This process is carried out by the E3-small ubiquitin-like modifier (SUMO) ligase protein inhibitor of activated STAT PIASy, which modifies the AMPKβ2 subunit by the attachment of SUMO2 but not SUMO1 moieties. Of interest, AMPKβ1 is not a substrate for this modification. We also demonstrate that sumoylation of AMPKβ2 enhances the activity of the trimeric α2β2γ1 AMPK complex. In addition, our results indicate that sumoylation is antagonist and competes with the ubiquitination of the AMPKβ2 subunit. This adds a new layer of complexity to the regulation of the activity of the AMPK complex, since conditions that promote ubiquitination result in inactivation, whereas those that promote sumoylation result in the activation of the AMPK complex.

Dysregulation of muscle lipid metabolism in rats selectively bred for low aerobic running capacity

2007 ◽  
Vol 292 (6) ◽  
pp. E1631-E1636 ◽  
Author(s):  
Fiona J. Spargo ◽  
Sean L. McGee ◽  
Nick Dzamko ◽  
Matthew J. Watt ◽  
Bruce E. Kemp ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Metabolic Diseases ◽  
Disease Risk ◽  
High Capacity ◽  
Whole Body ◽  
Nonesterified Fatty Acid ◽  
Endurance Running ◽  
Increased Risk ◽  
Amp Activated Protein Kinase

As substrate for evaluation of metabolic diseases, we developed novel rat models that contrast for endurance exercise capacity. Through two-way artificial selection, we created rodent phenotypes of intrinsically low-capacity runners (LCR) and high-capacity runners (HCR) that also differed markedly for cardiovascular and metabolic disease risk factors. Here, we determined skeletal muscle proteins with putative roles in lipid and carbohydrate metabolism to better understand the mechanisms underlying differences in whole body substrate handling between phenotypes. Animals ( generation 16) differed for endurance running capacity by 295%. LCR animals had higher resting plasma glucose (6.58 ± 0.45 vs. 6.09 ± 0.45 mmol/l), insulin (0.48 ± 0.03 vs. 0.32 ± 0.02 ng/ml), nonesterified fatty acid (0.57 ± 0.14 v 0.35 ± 0.05 mM), and triglyceride (TG; 0.47 ± 0.11 vs. 0.25 ± 0.08 mmol/l) concentrations (all P < 0.05). Muscle TG (72.3 ± 14.7 vs. 38.9 ± 6.2 mmol/kg dry muscle wt; P < 0.05) and diacylglycerol (96 ± 28 vs. 42 ± 8 pmol/mg dry muscle wt; P < 0.05) contents were elevated in LCR vs. HCR rats. Accompanying the greater lipid accretion in LCR was increased fatty acid translocase/CD36 content (1,014 ± 80 vs. 781 ± 70 arbitrary units; P < 0.05) and reduced TG lipase activity (0.158 ± 0.0125 vs. 0.274 ± 0.018 mmol·min−1·kg dry muscle wt−1; P < 0.05). Muscle glycogen, GLUT4 protein, and basal phosphorylation states of AMP-activated protein kinase-α1, AMP-activated protein kinase-α2, and acetyl-CoA carboxylase were similar in LCR and HCR. In conclusion, rats with low intrinsic aerobic capacity demonstrate abnormalities in lipid-handling capacity. These disruptions may, in part, be responsible for the increased risk of metabolic disorders observed in this phenotype.

scholarly journals Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status

Diabetologia ◽  
2011 ◽  
Vol 54 (12) ◽  
pp. 3101-3110 ◽  
Author(s):  
X. Stephenne ◽  
M. Foretz ◽  
N. Taleux ◽  
G. C. van der Zon ◽  
E. Sokal ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Human Hepatocytes ◽  
Energy Status ◽  
Cellular Energy ◽  
Primary Human Hepatocytes ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase and the metabolic syndrome

2005 ◽  
Vol 33 (2) ◽  
pp. 362-366 ◽  
Author(s):  
L.G.D. Fryer ◽  
D. Carling
Keyword(s):  
Protein Kinase ◽  
Glycogen Metabolism ◽  
Energy Utilization ◽  
Whole Body ◽  
Acid Oxidation ◽  
Type Ii ◽  
Glucose Levels ◽  
The Metabolic Syndrome ◽  
Amp Activated Protein Kinase ◽  
Body Energy

The occurrence of Type II (non-insulin-dependent) diabetes and obesity and their associated morbidities continue to increase and they are rapidly reaching epidemic proportions. AMPK (AMP-activated protein kinase) was initially thought of as an intracellular ‘fuel gauge’ responding to a decrease in the level of ATP by increasing energy production and decreasing energy utilization. Recent studies have shown that AMPK plays a role in controlling the whole body energy homoeostasis, including the regulation of plasma glucose levels, fatty acid oxidation and glycogen metabolism. In addition to its effects on the periphery, AMPK has been found to play a key role in the control of food intake through its regulation by hormones, including leptin, within the hypothalamus. The control of AMPK activity, therefore, provides an attractive target for therapeutic intervention in metabolic disorders such as obesity and Type II diabetes. Indeed, a number of physiological and pharmacological factors that are beneficial in these disorders have been shown to act, at least in part, through the activation of AMPK.

scholarly journals Interleukin-6 Expression by Hypothalamic Microglia in Multiple Inflammatory Contexts: A Systematic Review

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Vanessa C. D. Bobbo ◽  
Carlos P. Jara ◽  
Natália F. Mendes ◽  
Joseane Morari ◽  
Lício A. Velloso ◽  
...  
Keyword(s):  
Systematic Review ◽  
Interleukin 6 ◽  
Energy Homeostasis ◽  
Metabolic Diseases ◽  
Whole Body ◽  
Positive Energy ◽  
Anatomical Site ◽  
Control Food ◽  
Control Food Intake

Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of “injury-like” stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus.

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