AMPK in Health and Disease

2009 ◽  
Vol 89 (3) ◽  
pp. 1025-1078 ◽  
Author(s):  
Gregory R. Steinberg ◽  
Bruce E. Kemp
Keyword(s):  
Energy Balance ◽  
Stress Responses ◽  
Energy Demand ◽  
Dynamic Control ◽  
Cellular Level ◽  
Whole Body ◽  
Α Subunit ◽  
Ampk Signaling ◽  
Control Food Intake

The function and survival of all organisms is dependent on the dynamic control of energy metabolism, when energy demand is matched to energy supply. The AMP-activated protein kinase (AMPK) αβγ heterotrimer has emerged as an important integrator of signals that control energy balance through the regulation of multiple biochemical pathways in all eukaryotes. In this review, we begin with the discovery of the AMPK family and discuss the recent structural studies that have revealed the molecular basis for AMP binding to the enzyme's γ subunit. AMPK's regulation involves autoinhibitory features and phosphorylation of both the catalytic α subunit and the β-targeting subunit. We review the role of AMPK at the cellular level through examination of its many substrates and discuss how it controls cellular energy balance. We look at how AMPK integrates stress responses such as exercise as well as nutrient and hormonal signals to control food intake, energy expenditure, and substrate utilization at the whole body level. Lastly, we review the possible role of AMPK in multiple common diseases and the role of the new age of drugs targeting AMPK signaling.

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 Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes

2021 ◽  
Author(s):  
Verónica Hurtado-Carneiro ◽  
Ana Pérez-García ◽  
Elvira Álvarez ◽  
Carmen Sanz
Keyword(s):  
Type 2 Diabetes ◽  
Nutrient Availability ◽  
Energy Demand ◽  
Metabolic Response ◽  
Whole Body ◽  
Key Factor ◽  
Control Food ◽  
Control Food Intake

Cell survival depends on the constant challenge to match energy demands with nutrient availability. This process is mediated through a highly conserved network of metabolic fuel sensors that orchestrate both a cellular and whole-body energy balance. A mismatch between cellular energy demand and nutrient availability is a key factor in the development of type 2 diabetes, obesity, metabolic syndrome, and other associated pathologies; thus, understanding the fundamental mechanisms by which cells detect nutrient availability and energy demand may lead to the development of new treatments. This chapter reviews the role of the sensor PASK (protein kinase with PAS domain), analyzing its role in the mechanisms of adaptation to nutrient availability and the metabolic response in different organs (liver, hypothalamus) actively cooperating to control food intake, maintain glycaemia homeostasis, and prevent insulin resistance and weight gain.

scholarly journals The Role of AMPK Signaling in Brown Adipose Tissue Activation

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1122
Author(s):  
Jamie I. van der van der Vaart ◽  
Mariëtte R. Boon ◽  
Riekelt H. Houtkooper
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Whole Body ◽  
Ampk Signaling ◽  
Mitochondrial Homeostasis ◽  
Brown Adipose ◽  
Metabolic Stresses ◽  
Amp Activated Protein Kinase ◽  
Body Energy

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

The sweet side of AMPK signaling: regulation of GFAT1

2017 ◽  
Vol 474 (7) ◽  
pp. 1289-1292 ◽  
Author(s):  
John W. Scott ◽  
Jonathan S. Oakhill
Keyword(s):  
Energy Demand ◽  
Dynamic Control ◽  
Cellular Protein ◽  
Post Translational Modification ◽  
Nutrient Metabolism ◽  
Ampk Signaling ◽  
Biochemical Journal ◽  
Signaling Axis ◽  
Hexosamine Biosynthesis ◽  
Living Organisms

Maintaining a steady balance between nutrient supply and energy demand is essential for all living organisms and is achieved through the dynamic control of metabolic processes that produce and consume adenosine-5′-triphosphate (ATP), the universal currency of energy in all cells. A key sensor of cellular energy is the adenosine-5′-monophosphate (AMP)-activated protein kinase (AMPK), which is the core component of a signaling network that regulates energy and nutrient metabolism. AMPK is activated by metabolic stresses that decrease cellular ATP, and functions to restore energy balance by orchestrating a switch in metabolism away from anabolic pathways toward energy-generating catabolic processes. A new study published in a recent issue of Biochemical Journal by Zibrova et al. shows that glutamine:fructose-6-phosphate amidotransferase-1 (GFAT1), the rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), is a physiological substrate of AMPK. The HBP is an offshoot of the glycolytic pathway that drives the synthesis of uridine-5′-diphospho-N-acetylglucosamine, the requisite donor metabolite needed for dynamic β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of cellular proteins. O-GlcNAcylation is a nutrient-sensitive post-translational modification that, like phosphorylation, regulates numerous intracellular processes. Zibrova et al. show that inhibitory phosphorylation of the GFAT1 residue Ser243 by AMPK in response to physiological or small-molecule activators leads to a reduction in cellular protein O-GlcNAcylation. Further work revealed that AMPK-dependent phosphorylation of GFAT1 promotes angiogenesis in endothelial cells. This elegant study demonstrates that the AMPK–GFAT1 signaling axis serves as an important communication point between two nutrient-sensitive signaling pathways and is likely to play a significant role in controlling physiological processes in many other tissues.

scholarly journals Whole-Body Metabolism, Carbohydrate Utilization, and Caloric Energy Balance After Sport Concussion: A Pilot Study

2020 ◽  
Vol 12 (4) ◽  
pp. 382-389
Author(s):  
Samuel R. Walton ◽  
Steven K. Malin ◽  
Sibylle Kranz ◽  
Donna K. Broshek ◽  
Jay Hertel ◽  
...  
Keyword(s):  
Pilot Study ◽  
Energy Balance ◽  
Energy Demand ◽  
Dietary Intervention ◽  
Collegiate Athletes ◽  
Return To Play ◽  
Whole Body ◽  
Carbohydrate Utilization ◽  
Sport Concussion ◽  
Group Sex

Background: Sport concussion (SC) causes an energy crisis in the brain by increasing energy demand, decreasing energy supply, and altering metabolic resources. Whole-body resting metabolic rate (RMR) is elevated after more severe brain injuries, but RMR changes are unknown after SC. The purpose of this study was to longitudinally examine energy-related changes in collegiate athletes after SC. Hypothesis: RMR and energy consumption will increase acutely after SC and will return to control levels with recovery. Study Design: Case-control study. Level of Evidence: Level 4. Methods: A total of 20 collegiate athletes with SC (mean age, 19.3 ± 1.08 years; mean height, 1.77 ± 0.11 m; mean weight, 79.6 ± 23.37 kg; 55% female) were compared with 20 matched controls (mean age, 20.8 ± 2.17 years; mean height, 1.77 ± 0.10 m; mean weight, 81.9 ± 23.45 kg; 55% female). RMR, percentage carbohydrate use (%CHO), and energy balance (EBal; ratio between caloric consumption and expenditure) were assessed 3 times: T1, ≤72 hours after SC; T2, 7 days after T1; and TF, after symptom resolution. A 2 × 2 × 3 (group × sex × time) multivariate analysis of variance assessed RMR, %CHO, and EBal. Changes in RMR, %CHO, and EBal (T1 to TF) were correlated with days to symptom-free and days to return to play in the concussed group. Results: Women reported being symptom-free (median, 6 days; range, 3-10 days) sooner than men (median, 11 days; range, 7-16 days). RMR and %CHO did not differ across time between groups or for group × sex interaction. SC participants had higher EBal than controls at T1 ( P = 0.016) and T2 ( P = 0.010). In men with SC, increasing %CHO over time correlated with days to symptom-free ( r = 0.735 and P = 0.038, respectively) and days to return to play ( r = 0.829 and P = 0.021, respectively). Conclusion: Participants with SC were in energy surplus acutely after injury. Although women recovered more quickly than men, men had carbohydrate metabolism changes that correlated with recovery time. Clinical Relevance: This pilot study shows that male and female student-athletes may have differing physiologic responses to SC and that there may be a role for dietary intervention to improve clinical outcomes after SC.

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 Epithelial Ca2+ channel expression and Ca2+ uptake in developing zebrafish

2005 ◽  
Vol 289 (4) ◽  
pp. R1202-R1211 ◽  
Author(s):  
Tien-Chien Pan ◽  
Bo-Kai Liao ◽  
Chang-Jen Huang ◽  
Li-Yih Lin ◽  
Pung-Pung Hwang
Keyword(s):  
Danio Rerio ◽  
Yolk Sac ◽  
Whole Body ◽  
Zebrafish Embryos ◽  
Uptake Mechanism ◽  
Α Subunit ◽  
Channel Expression ◽  
Gill Filaments ◽  
Rapid Amplification

The purpose of the present work was to study the possible role of the epithelial Ca2+ channel (ECaC) in the Ca2+ uptake mechanism in developing zebrafish ( Danio rerio). With rapid amplification of cDNA ends, full-length cDNA encoding the ECaC of zebrafish (zECaC) was cloned and sequenced. The cloned zECaC was 2,578 bp in length and encoded a protein of 709 amino acids that showed up to 73% identity with previously described vertebrate ECaCs. The zECaC was found to be expressed in all tissues examined and began to be expressed in the skin covering the yolk sac of embryos at 24 h postfertilization (hpf). zECaC-expressing cells expanded to cover the skin of the entire yolk sac after embryonic development and began to occur in the gill filaments at 96 hpf, and thereafter zECaC-expressing cells rapidly increased in both gills and yolk sac skin. Corresponding to ECaC expression profile, the Ca2+ influx and content began to increase at 36–72 hpf. Incubating zebrafish embryos in low-Ca2+ (0.02 mM) freshwater caused upregulation of the whole body Ca2+ influx and zECaC expression in both gills and skin. Colocalization of zECaC mRNA and the Na+-K+-ATPase α-subunit (a marker for mitochondria-rich cells) indicated that only a portion of the mitochondria-rich cells expressed zECaC mRNA. These results suggest that the zECaC plays a key role in Ca2+ absorption in developing zebrafish.

Role of hypothalamic autophagy in the control of whole body energy balance

2013 ◽  
Vol 14 (4) ◽  
pp. 377-386 ◽  
Author(s):  
Min-Seon Kim ◽  
Wenying Quan ◽  
Myung-Shik Lee
Keyword(s):  
Energy Balance ◽  
Whole Body ◽  
Body Energy

scholarly journals Fat specific adipose triglyceride lipase is necessary for iron-mediated lipolysis and lipid mobilization in response to negative energy balance

2021 ◽  
Author(s):  
Alicia R Romero ◽  
Andre Mu ◽  
Janelle S Ayres
Keyword(s):  
Energy Balance ◽  
Negative Energy ◽  
Activity Level ◽  
Negative Energy Balance ◽  
Whole Body ◽  
Adipose Triglyceride Lipase ◽  
Dietary Iron ◽  
Lipid Mobilization ◽  
Triglyceride Lipase

Maintenance of energy balance is essential for the overall health of an organism. In mammals, both negative and positive energy balance are associated with disease states. To maintain their energy balance within a defined homeostatic setpoint, mammals have evolved complex regulatory mechanisms that control energy intake and expenditure. Traditionally, studies have focused on understanding the role of macronutrient physiology in energy balance. In the present study, we examined the role of the essential micronutrient iron in regulating energy balance. Using a dietary model, we found that a short course of excess dietary iron caused a negative energy balance resulting in a severe whole body wasting phenotype. This disruption in energy balance was due to an iron dependent increase in energy expenditure caused by a heightened basal metabolic rate and activity level. Using a transgenic mouse model lacking adipose triglyceride lipase (ATGL) specifically in fat tissue, we found that to meet the increased energetic demands, dietary iron caused increased lipid utilization that required fat specific ATGL-mediated lipid mobilization and wasting of subcutaneous white adipose tissue deposits. When fed dietary iron, mice lacking fat-specific ATGL activity were protected from fat wasting, and developed a severe cachectic response that is necessary to meet the increased energetic demands caused by the dietary regimen. Our work highlights the multi-faceted role of iron regulation of organismal metabolism and provides a novel in vivo mechanism for micronutrient control of lipolysis that is necessary for regulating mammalian energy balance.

Allosteric regulation of AMP-activated protein kinase by adenylate nucleotides and small-molecule drugs

2019 ◽  
Vol 47 (2) ◽  
pp. 733-741 ◽  
Author(s):  
Ana Laura de Souza Almeida Matos ◽  
Jonathan S. Oakhill ◽  
José Moreira ◽  
Kim Loh ◽  
Sandra Galic ◽  
...  
Keyword(s):  
Energy Balance ◽  
Protein Kinase ◽  
Small Molecule ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Cellular Level ◽  
Whole Body ◽  
Allosteric Activation ◽  
Small Molecule Drugs ◽  
Body Energy

Abstract The AMP (adenosine 5′-monophosphate)-activated protein kinase (AMPK) is a key regulator of cellular and whole-body energy homeostasis that co-ordinates metabolic processes to ensure energy supply meets demand. At the cellular level, AMPK is activated by metabolic stresses that increase AMP or adenosine 5′-diphosphate (ADP) coupled with falling adenosine 5′-triphosphate (ATP) and acts to restore energy balance by choreographing a shift in metabolism in favour of energy-producing catabolic pathways while inhibiting non-essential anabolic processes. AMPK also regulates systemic energy balance and is activated by hormones and nutritional signals in the hypothalamus to control appetite and body weight. Failure to maintain energy balance plays an important role in chronic diseases such as obesity, type 2 diabetes and inflammatory disorders, which has prompted a major drive to develop pharmacological activators of AMPK. An array of small-molecule allosteric activators has now been developed, several of which can activate AMPK by direct allosteric activation, independently of Thr172 phosphorylation, which was previously regarded as indispensable for AMPK activity. In this review, we summarise the state-of-the-art regarding our understanding of the molecular mechanisms that govern direct allosteric activation of AMPK by adenylate nucleotides and small-molecule drugs.

Sign in / Sign up

Export Citation Format

Share Document