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.

Exercise and MEF2–HDAC interactions

2007 ◽  
Vol 32 (5) ◽  
pp. 852-856 ◽  
Author(s):  
Sean L. McGee
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Nuclear Export ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Positive Health ◽  
Exercise Induced ◽  
Amp Activated Protein Kinase ◽  
Body Energy ◽  
Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

AMP-activated protein kinase regulation and action in skeletal muscle during exercise

2003 ◽  
Vol 31 (1) ◽  
pp. 191-195 ◽  
Author(s):  
N. Musi ◽  
H. Yu ◽  
L.J. Goodyear
Keyword(s):  
Protein Kinase ◽  
Exercise Training ◽  
Metabolic Pathways ◽  
Acute Exercise ◽  
Glycogen Content ◽  
Glycogen Metabolism ◽  
Acid Oxidation ◽  
Ampk Activity ◽  
Energy Sensing ◽  
Amp Activated Protein Kinase

Physical exercise increases muscle glucose uptake, enhances insulin sensitivity and leads to fatty acid oxidation in muscle. The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is strongly activated during muscle contraction due to acute decreases in ATP/AMP and phosphocreatine/creatine ratios. Accumulating evidence suggests that AMPK plays an important role in mediating these metabolic processes. Furthermore, AMPK has been implicated in regulating gene transcription and therefore may play a role in some of the cellular adaptations to training exercise. There is also evidence that changes in AMPK activity result in altered cellular glycogen content, suggesting that this enzyme regulates glycogen metabolism. Recent studies have shown that the magnitude of AMPK activation and associated metabolic responses are affected by factors such as glycogen content, exercise training and fibre type. In summary, AMPK regulates several metabolic pathways during acute exercise and modifies the expression of many genes involved in the adaptive changes to exercise training.

scholarly journals Skeletal muscle AMP-activated protein kinase γ1H151R overexpression enhances whole body energy homeostasis and insulin sensitivity

2015 ◽  
Vol 309 (7) ◽  
pp. E679-E690 ◽  
Author(s):  
Milena Schönke ◽  
Martin G. Myers ◽  
Juleen R. Zierath ◽  
Marie Björnholm
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Transgenic Mice ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Α Subunit ◽  
Peripheral Tissues ◽  
Amp Activated Protein Kinase ◽  
Body Energy

AMP-activated protein kinase (AMPK) is a major sensor of energy homeostasis and stimulates ATP-generating processes such as lipid oxidation and glycolysis in peripheral tissues. The heterotrimeric enzyme consists of a catalytic α-subunit, a β-subunit that is important for enzyme activity, and a noncatalytic γ-subunit that binds AMP and activates the AMPK complex. We generated a skeletal muscle Cre-inducible transgenic mouse model expressing a mutant γ1-subunit (AMPKγ1H151R), resulting in chronic AMPK activation. The expression of the predominant AMPKγ3 isoform in skeletal muscle was reduced in extensor digitorum longus (EDL) muscle (81–83%) of AMPKγ1H151R transgenic mice, whereas the abundance and phosphorylation of the AMPK target acetyl-CoA carboxylase was increased in tibialis anterior muscle. Glycogen content was increased 10-fold in gastrocnemius muscle. Whole body carbohydrate oxidation was increased by 11%, and whereas glucose tolerance was unaffected, insulin sensitivity was increased in AMPKγ1H151R transgenic mice. Furthermore, perigonadal white adipose tissue mass and serum leptin were reduced in female AMPKγ1H151R transgenic mice by 38 and 51% respectively. Conversely, in male AMPKγ1H151R transgenic mice, food intake was increased (14%), but body weight and body composition were unaltered, presumably because of increased energy expenditure. In conclusion, transgenic activation of skeletal muscle AMPKγ1 in this model plays an important sex-specific role in skeletal muscle metabolism and whole body energy homeostasis.

Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance

2011 ◽  
Vol 12 (3) ◽  
pp. 127-140 ◽  
Author(s):  
Pablo Blanco Martínez de Morentin ◽  
Carmen R. González ◽  
Asisk K. Saha ◽  
Luís Martins ◽  
Carlos Diéguez ◽  
...  
Keyword(s):  
Energy Balance ◽  
Protein Kinase ◽  
Whole Body ◽  
Amp Activated Protein Kinase ◽  
Body Energy

scholarly journals The regulation and function of the NUAK family

2013 ◽  
Vol 51 (2) ◽  
pp. R15-R22 ◽  
Author(s):  
Xianglan Sun ◽  
Ling Gao ◽  
Hung-Yu Chien ◽  
Wan-Chun Li ◽  
Jiajun Zhao
Keyword(s):  
Protein Kinase ◽  
Structural Organization ◽  
Energy Homeostasis ◽  
Catalytic Domain ◽  
Whole Body ◽  
Upstream Kinase ◽  
Liver Kinase B1 ◽  
And Function ◽  
Amp Activated Protein Kinase ◽  
Body Energy

AMP-activated protein kinase (AMPK) is a critical regulator of cellular and whole-body energy homeostasis. Twelve AMPK-related kinases (ARKs; BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4, and MELK) have been identified recently. These kinases show a similar structural organization, including an N-terminal catalytic domain, followed by a ubiquitin-associated domain and a C-terminal spacer sequence, which in some cases also contains a kinase-associated domain 1. Eleven of the ARKs are phosphorylated and activated by the master upstream kinase liver kinase B1. However, most of these ARKs are largely unknown, and the NUAK family seems to have different regulations and functions. This review contains a brief discussion of the NUAK family including the specific characteristics of NUAK1 and NUAK2.

scholarly journals Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation

2013 ◽  
Vol 124 (8) ◽  
pp. 491-507 ◽  
Author(s):  
Silvia Bijland ◽  
Sarah J. Mancini ◽  
Ian P. Salt
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Protein Kinase ◽  
Caloric Intake ◽  
Whole Body ◽  
Acid Oxidation ◽  
Metabolic Dysfunction ◽  
Nutrient Metabolism ◽  
Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. AMPK phosphorylates and regulates many proteins concerned with nutrient metabolism, largely acting to suppress anabolic ATP-consuming pathways while stimulating catabolic ATP-generating pathways. This has led to considerable interest in AMPK as a therapeutic target for the metabolic dysfunction observed in obesity and insulin resistance. The role of AMPK in skeletal muscle and the liver has been extensively studied, such that AMPK has been demonstrated to inhibit synthesis of fatty acids, cholesterol and isoprenoids, hepatic gluconeogenesis and translation while increasing fatty acid oxidation, muscle glucose transport, mitochondrial biogenesis and caloric intake. The role of AMPK in the other principal metabolic and insulin-sensitive tissue, adipose, remains poorly characterized in comparison, yet increasing evidence supports an important role for AMPK in adipose tissue function. Obesity is characterized by hypertrophy of adipocytes and the development of a chronic sub-clinical pro-inflammatory environment in adipose tissue, leading to increased infiltration of immune cells. This combination of dysfunctional hypertrophic adipocytes and a pro-inflammatory environment contributes to insulin resistance and the development of Type 2 diabetes. Exciting recent studies indicate that AMPK may not only influence metabolism in adipocytes, but also act to suppress this pro-inflammatory environment, such that targeting AMPK in adipose tissue may be desirable to normalize adipose dysfunction and inflammation. In the present review, we discuss the role of AMPK in adipose tissue, focussing on the regulation of carbohydrate and lipid metabolism, adipogenesis and pro-inflammatory pathways in physiological and pathophysiological conditions.

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.

scholarly journals SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK

2017 ◽  
Vol 313 (4) ◽  
pp. E493-E505 ◽  
Author(s):  
Xiaona Cui ◽  
Lu Yao ◽  
Xiaoying Yang ◽  
Yong Gao ◽  
Fude Fang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Whole Body ◽  
Acid Oxidation ◽  
Metabolic Homeostasis ◽  
Lipid Uptake ◽  
Loss Of Function ◽  
Knockout Mouse Model ◽  
Expression Of Genes ◽  
Amp Activated Protein Kinase ◽  
Body Energy

Because of the mass and functions in metabolism, skeletal muscle is one of the major organs regulating whole body metabolic homeostasis. SIRT6, a histone deacetylase, has been shown to regulate metabolism in liver and brain; however, its specific role in skeletal muscle is undetermined. In the present study we explored physiological function of SIRT6 in muscle. We generated a muscle-specific SIRT6 knockout mouse model. The mice with SIRT6 deficiency in muscle displayed impaired glucose homeostasis and insulin sensitivity, attenuated whole body energy expenditure, and weakened exercise performance. Mechanistically, deletion of SIRT6 in muscle decreased expression of genes involved in glucose and lipid uptake, fatty acid oxidation, and mitochondrial oxidative phosphorylation in muscle cells because of the reduced AMP-activated protein kinase (AMPK) activity. In contrast, overexpression of SIRT6 in C2C12 myotubes activates AMPK. Our results from both gain- and loss-of-function experiments identify SIRT6 as a physiological regulator of muscle mitochondrial function. These findings indicate that SIRT6 is a potential therapeutic target for treatment of type 2 diabetes mellitus.

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.

Bypassing the glucose/fatty acid cycle: AMP-activated protein kinase

2003 ◽  
Vol 31 (6) ◽  
pp. 1157-1160 ◽  
Author(s):  
D. Carling ◽  
L.G.D. Fryer ◽  
A. Woods ◽  
T. Daniel ◽  
S.L.C. Jarvie ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Metabolic Regulation ◽  
Muscle Activation ◽  
Glycogen Metabolism ◽  
Acid Oxidation ◽  
Acid Cycle ◽  
Glucose Fatty Acid Cycle ◽  
Amp Activated Protein Kinase

The AMPK (AMP-activated protein kinase) cascade plays a key role in regulating energy metabolism. Conditions which cause a decrease in the ATP/AMP ratio lead to activation of AMPK. Once activated, AMPK initiates a series of responses that act to restore the energy balance of the cell. In skeletal muscle, activation of AMPK increases both glucose uptake and fatty acid oxidation, raising the possibility that AMPK can bypass the glucose/fatty acid cycle. This review focuses on the role of AMPK in the regulation of glucose and fatty acid metabolism in muscle. Recently, naturally occurring mutations within the γ isoforms have been identified which lead to altered metabolic regulation in cardiac and skeletal muscle and suggest an important role for the kinase in regulating glycogen metabolism.

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