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.

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.

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.

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 Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

2013 ◽  
Vol 220 (1) ◽  
pp. 13-24 ◽  
Author(s):  
Anaies Nazarians-Armavil ◽  
Jennifer A Chalmers ◽  
Claire B Lee ◽  
Wenqing Ye ◽  
Denise D Belsham
Keyword(s):  
Insulin Resistance ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Second Messengers ◽  
Mrna Level ◽  
Neuronal Cell ◽  
Whole Body ◽  
Cell Models ◽  
Metabolic Hormones ◽  
Body Energy

POMC neurons play a central role in the maintenance of whole-body energy homeostasis. This balance requires proper regulation of POMC neurons by metabolic hormones, such as insulin. However, the heterogeneous cellular population of the intact hypothalamus presents challenges for examining the molecular mechanisms underlying the potent anorexigenic effects of POMC neurons, and there is currently a complete lack of mature POMC neuronal cell models for study. To this end, we have generated novel, immortalized, adult-derived POMC-expressing/α-MSH-secreting cell models, mHypoA-POMC/GFP lines 1–4, representing the fluorescence-activated cell-sorted POMC population from primary POMC-eGFP mouse hypothalamus. The presence of Pomc mRNA in these cell lines was confirmed, and α-MSH was detected via immunofluorescence. α-MSH secretion in the mHypoA-POMC/GFP-1 was found to increase in response to 10 ng/ml ciliary neurotrophic factor (CNTF) or 10 nM insulin as determined by enzyme immunoassay. Further experiments using the mHypoA-POMC/GFP-1 cell line revealed that 10 ng/ml CNTF increases Pomc mRNA at 1 and 2 h after treatment, whereas insulin elicited an increase in Pomc mRNA level and decreases in insulin receptor (Insr (Ir)) mRNA level at 4 h. Furthermore, the activation of IR-mediated downstream second messengers was examined by western blot analysis, following the induction of cellular insulin resistance, which resulted in a loss of insulin-mediated regulation of Pomc and Ir mRNAs. The development of these immortalized neurons will be invaluable for the elucidation of the cellular and molecular mechanisms that underlie POMC neuronal function under normal and perturbed physiological conditions.

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 Pleiotropic Potential of BDNF beyond Neurons: Implication for a Healthy Mind in a Healthy Body

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1256
Author(s):  
Maria Carmela Di Rosa ◽  
Stefania Zimbone ◽  
Miriam Wissam Saab ◽  
Marianna Flora Tomasello
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Cellular Level ◽  
Adaptive Responses ◽  
Peripheral Tissues ◽  
The Central Nervous System ◽  
The Many ◽  
Feeding Control ◽  
Healthy Body

Brain-derived neurotrophic factor (BDNF) represents one of the most widely studied neurotrophins because of the many mechanisms in which it is involved. Among these, a growing body of evidence indicates BDNF as a pleiotropic signaling molecule and unveils non-negligible implications in the regulation of energy balance. BDNF and its receptor are extensively expressed in the hypothalamus, regions where peripheral signals, associated with feeding control and metabolism activation, and are integrated to elaborate anorexigenic and orexigenic effects. Thus, BDNF coordinates adaptive responses to fluctuations in energy intake and expenditure, connecting the central nervous system with peripheral tissues, including muscle, liver, and the adipose tissue in a complex operational network. This review discusses the latest literature dealing with the involvement of BDNF in the maintenance of energy balance. We have focused on the physiological and molecular mechanisms by which BDNF: (I) controls the mitochondrial function and dynamics; (II) influences thermogenesis and tissue differentiation; (III) mediates the effects of exercise on cognitive functions; and (IV) modulates insulin sensitivity and glucose transport at the cellular level. Deepening the understanding of the mechanisms exploited to maintain energy homeostasis will lay the groundwork for the development of novel therapeutical approaches to help people to maintain a healthy mind in a healthy body.

Omega-3 Fatty Acids and Adipose Tissue: Inflammation and Browning

2020 ◽  
Vol 40 (1) ◽  
pp. 25-49 ◽  
Author(s):  
Nishan Sudheera Kalupahana ◽  
Bimba Lakmini Goonapienuwala ◽  
Naima Moustaid-Moussa
Keyword(s):  
Fatty Acids ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Metabolic Regulation ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Omega 3 ◽  
Brown Adipose ◽  
Body Energy

White adipose tissue (WAT) and brown adipose tissue (BAT) are involved in whole-body energy homeostasis and metabolic regulation. Changes to mass and function of these tissues impact glucose homeostasis and whole-body energy balance during development of obesity, weight loss, and subsequent weight regain. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which have known hypotriglyceridemic and cardioprotective effects, can also impact WAT and BAT function. In rodent models, these fatty acids alleviate obesity-associated WAT inflammation, improve energy metabolism, and increase thermogenic markers in BAT. Emerging evidence suggests that ω-3 PUFAs can also modulate gut microbiota impacting WAT function and adiposity. This review discusses molecular mechanisms, implications of these findings, translation to humans, and future work, especially with reference to the potential of these fatty acids in weight loss maintenance.

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 Baicalin Attenuates High Fat Diet-Induced Obesity and Liver Dysfunction: Dose-Response and Potential Role of CaMKKβ/AMPK/ACC Pathway

2015 ◽  
Vol 35 (6) ◽  
pp. 2349-2359 ◽  
Author(s):  
Youli Xi ◽  
Miaozong Wu ◽  
Hongxia Li ◽  
Siqi Dong ◽  
Erfei Luo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Liver Steatosis ◽  
Serum Levels ◽  
Whole Body ◽  
Therapeutic Effects ◽  
High Fat ◽  
Dependent Protein

Background/Aims: Obesity-associated fatty liver disease affects millions of individuals. This study aimed to evaluate the therapeutic effects of baicalin to treat obesity and fatty liver in high fat diet-induced obese mice, and to study the potential molecular mechanisms. Methods: High fat diet-induced obese animals were treated with different doses of baicalin (100, 200 and 400 mg/kg/d). Whole body, fat pad and liver were weighed. Hyperlipidemia, liver steatosis, liver function, and hepatic Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ) / AMP-activated protein kinase (AMPK) / acetyl-CoA carboxylase (ACC) were further evaluated. Results: Baicalin significantly decreased liver, epididymal fat and body weights in high fat diet-fed mice, which were associated with decreased serum levels of triglycerides, total cholesterol, LDL, alanine transaminase and aspartate transaminase, but increased serum HDL level. Pathological analysis revealed baicalin dose-dependently decreased the degree of hepatic steatosis, with predominantly diminished macrovesicular steatosis at lower dose but both macrovesicular and microvesicular steatoses at higher dose of baicalin. Baicalin dose-dependently inhibited hepatic CaMKKβ/AMPK/ACC pathway. Conclusion: These data suggest that baicalin up to 400 mg/kg/d is safe and able to decrease the degree of obesity and fatty liver diseases. Hepatic CaMKKβ/AMPK/ACC pathway may mediate the therapeutic effects of baicalin in high fat diet animal model.

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