Detection of AMP-activated protein kinase α1 by isoelectric focusing in sera of patients with metabolic diseases

AMP-activated protein kinase (AMPK) is a master regulator of energy homeostasis and a promising drug target for managing metabolic diseases such as type 2 diabetes. Many pharmacological AMPK activators, and possibly unidentified physiological metabolites, bind to the allosteric drug and metabolite (ADaM) site at the interface between the kinase domain (KD) in the α-subunit and the carbohydrate-binding module (CBM) in the β-subunit. Here, using double electron–electron resonance (DEER) spectroscopy, we demonstrate that the CBM–KD interaction is partially dissociated and the interface highly disordered in the absence of pharmacological ADaM site activators as inferred from a low depth of modulation and broad DEER distance distributions. ADaM site ligands such as 991, and to a lesser degree phosphorylation, stabilize the KD–CBM association and strikingly reduce conformational heterogeneity in the ADaM site. Our findings that the ADaM site, formed by the KD–CBM interaction, can be modulated by diverse ligands and by phosphorylation suggest that it may function as a hub for integrating regulatory signals.

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AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease

Clinical Science ◽

10.1042/cs20080066 ◽

2009 ◽

Vol 116 (8) ◽

pp. 607-620 ◽

Cited By ~ 109

Author(s):

Aaron K. F. Wong ◽

Jacqueline Howie ◽

John R. Petrie ◽

Chim C. Lang

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Elongation Factor ◽

Cardiometabolic Disease ◽

Acid Oxidation ◽

Ampk Activation ◽

Atp Production ◽

Beneficial Effects ◽

Eukaryotic Elongation Factor ◽

Amp Activated Protein Kinase

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

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AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases

The Journal of Lipid Research ◽

10.1194/jlr.r025882 ◽

2012 ◽

Vol 53 (12) ◽

pp. 2490-2514 ◽

Cited By ~ 142

Author(s):

Rai Ajit K. Srivastava ◽

Stephen L. Pinkosky ◽

Sergey Filippov ◽

Jeffrey C. Hanselman ◽

Clay T. Cramer ◽

...

Keyword(s):

Protein Kinase ◽

Carbohydrate Metabolism ◽

Drug Target ◽

Metabolic Diseases ◽

Amp Activated Protein Kinase

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Unraveling the actions of AMP-activated protein kinase in metabolic diseases: Systemic to molecular insights

Metabolism ◽

10.1016/j.metabol.2016.01.005 ◽

2016 ◽

Vol 65 (5) ◽

pp. 634-645 ◽

Cited By ~ 26

Author(s):

Karen A. Weikel ◽

Neil B. Ruderman ◽

José M. Cacicedo

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Amp Activated Protein Kinase

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Ganoderma lucidum Extract Reduces Insulin Resistance by Enhancing AMPK Activation in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu12113338 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3338

Author(s):

Hyeon A Lee ◽

Jae-Han Cho ◽

Qonita Afinanisa ◽

Gi-Hong An ◽

Jae-Gu Han ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Glucose Metabolism ◽

High Fat Diet ◽

Ganoderma Lucidum ◽

Fatty Acid Synthase ◽

Metabolic Diseases ◽

Ampk Activation ◽

High Fat ◽

Amp Activated Protein Kinase

Ganoderma lucidum is used widely in oriental medicine to treat obesity and metabolic diseases. Bioactive substances extracted from G. lucidum have been shown to ameliorate dyslipidemia, insulin resistance, and type 2 diabetes in mice via multiple 5′ AMP-activated protein kinase (AMPK)-mediated mechanisms; however, further studies are required to elucidate the anti-obesity effects of G. lucidum in vivo. In this study, we demonstrated that 3% G. lucidum extract powder (GEP) can be used to prevent obesity and insulin resistance in a mouse model. C57BL/6 mice were provided with a normal diet (ND) or a high-fat diet (HFD) supplemented with 1, 3, or 5% GEP for 12 weeks and the effect of GEP on body weight, liver, adipose tissue, adipokines, insulin and glucose tolerance (ITT and GTT), glucose uptake, glucose-metabolism related proteins, and lipogenesis related genes was examined. GEP administration was found to reduce weight gain in the liver and fat tissues of the mice. In addition, serum parameters were significantly lower in the 3% and 5% GEP mice groups than in those fed a HFD alone, whereas adiponectin levels were significantly higher. We also observed that GEP improved glucose metabolism, reduced lipid accumulation in the liver, and reduced adipocyte size. These effects may have been mediated by enhanced AMPK activation, which attenuated the transcription and translation of lipogenic genes such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), and sterol regulatory element-binding protein-1c (SREBP1c). Moreover, AMP-activated protein kinase (AMPK) activation increased acetyl-CoA carboxylase (ACC), insulin receptor (IR), IR substrate 1 (IRS1), and Akt protein expression and activation, as well as glucose transporter type 1/4 (GLUT1/4) protein production, thereby improving insulin sensitivity and glucose metabolism. Together, these findings demonstrate that G. lucidum may effectively prevent obesity and suppress obesity-induced insulin resistance via AMPK activation.

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Isoginkgetin enhances adiponectin secretion from differentiated adiposarcoma cells via a novel pathway involving AMP-activated protein kinase

Journal of Endocrinology ◽

10.1677/joe-07-0200 ◽

2007 ◽

Vol 194 (3) ◽

pp. 569-578 ◽

Cited By ~ 28

Author(s):

Guohong Liu ◽

Mirta Grifman ◽

James Macdonald ◽

Peter Moller ◽

Flossie Wong-Staal ◽

...

Keyword(s):

Protein Kinase ◽

Metabolic Diseases ◽

Diabetic Patients ◽

Peroxisome Proliferators ◽

Slight Effect ◽

Increase Insulin Sensitivity ◽

Plasma Adiponectin ◽

Attractive Candidate ◽

Diabetic Treatment ◽

Amp Activated Protein Kinase

Adiponectin is an anti-diabetic hormone secreted byadipocytes. Circulating adiponectin levels are lower in obese and type II diabetic patients than in healthy people. Weight loss or thiazolidinedione treatment increases plasma adiponectin levels. Animal models and human studies suggest that elevated adiponectin levels increase insulin sensitivity. We screened a library of drug-like compounds and natural products for novel agents enhancing adiponectin production. We identified isoginkgetin, a compound derived from the leaves of Ginkgo biloba, to up-regulate adiponectin secretion with potency comparable to that of rosiglitazone, a known modulator of adiponectin production. However, unlike rosiglitazone, peroxisome proliferators-activated receptor γ activity seems not required for the action of isoginkgetin, and isoginkgetin has only a slight effect on adipogenesis, which makes it an attractive candidate for anti-diabetic treatment. Further investigation revealed that both isoginkgetin and rosiglitazone activate AMP-activated protein kinase (AMPK) in adipocytes. Our findings suggest a novel mechanism for the elevation of adiponectin by isoginkgetin, which is different from that of rosiglitazone. Furthermore, this novel mechanism for adiponectin regulation involving AMPK can potentially facilitate new understanding of metabolic diseases and identification of new targets, as well as agents that increase plasma adiponectin levels.

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Differential Role of AMP-Activated Protein Kinase in Brown and White Adipose Tissue Components and Its Consequences in Metabolic Diseases

Journal of Diabetes & Metabolism ◽

10.4172/2155-6156.1000406 ◽

2016 ◽

Vol 07 (07) ◽

Author(s):

Monireh Dashty

Keyword(s):

Adipose Tissue ◽

Protein Kinase ◽

White Adipose Tissue ◽

Metabolic Diseases ◽

Amp Activated Protein Kinase

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00702.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1631-E1636 ◽

Cited By ~ 10

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.

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

Essays in Biochemistry ◽

10.1042/bse0430121 ◽

2007 ◽

Vol 43 ◽

pp. 121-138 ◽

Cited By ~ 50

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.

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