Beyond Energy Homeostasis: the Expanding Role of AMP-Activated Protein Kinase in Regulating Metabolism

Carling, David; Viollet, Benoı̂t

doi:10.1016/j.cmet.2015.05.005

Cited by 74 publications

(58 citation statements)

References 31 publications

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“…b Interaction analysis of BCK and ∆BCK with JWA using both split-ubiquitin Y2H assays. c Interaction analysis of BCK and ∆BCK with VAMP2 (V2), VAMP3 (V3) and JWA using the soluble Split-Trp system and to diminish ATP expenditure (in general by decreasing anabolic pathways) (Mihaylova and Shaw 2011;Carling and Viollet 2015;Hardie and Ashford 2014;Hardie et al 2016). We have found that activated AMPK interacts with and phosphorylates and BCK with rapid kinetics (Fig.…”

Section: Regulation Of Bck Localization By Phosphorylationmentioning

confidence: 87%

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

et al. 2016

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There is an increasing body of evidence for local circuits of ATP generation and consumption that are largely independent of global cellular ATP levels. These are mostly based on the formation of multiprotein(-lipid) complexes and diffusion limitations existing in cells at different levels of organization, e.g., due to the viscosity of the cytosolic medium, macromolecular crowding, multiple and bulky intracellular structures, or controlled permeability across membranes. Enzymes generating ATP or GTP are found associated with ATPases and GTPases enabling the direct fueling of these energy-dependent processes, and thereby implying that it is the local and not the global concentration of high-energy metabolites that is functionally relevant. A paradigm for such microcompartmentation is creatine kinase (CK). Cytosolic and mitochondrial isoforms of CK constitute a well established energy buffering and shuttling system whose functions are very much based on local association of CK isoforms with ATP-providing and ATP-consuming processes. Here we review current knowledge on the subcellular localization and direct protein and lipid interactions of CK isoforms, in particular about cytosolic brain-type CK (BCK) much less is known compared to muscle-type CK (MCK). We further present novel data on BCK, based on three different experimental approaches: (1) co-purification experiments, suggesting association of BCK with membrane structures such as synaptic vesicles and mitochondria, involving hydrophobic and electrostatic interactions, respectively; (2) yeast-two-hybrid analysis using cytosolic split-protein assays and the identifying membrane proteins VAMP2, VAMP3 and JWA as putative BCK interaction partners; and (3) phosphorylation experiments, showing that the cellular energy sensor AMP-activated protein kinase (AMPK) is able to phosphorylate BCK at serine 6 to trigger BCK localization at the ER, in close vicinity of the highly energy-demanding Ca(2+) ATPase pump. Thus, membrane localization of BCK seems to be an important and regulated feature for the fueling of membrane-located, ATP-dependent processes, stressing again the importance of local rather than global ATP concentrations.

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Section: Regulation Of Bck Localization By Phosphorylationmentioning

confidence: 87%

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

et al. 2016

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“…ATP consuming) and catabolic (i.e. ATP producing) pathways (104). AMPK has also emerged as a hypothalamic energy sensor that influences both food intake and energy expenditure (102,103,105).…”

Section: Body Composition Energy Expenditure and Food Intakementioning

confidence: 99%

Energy balance, body composition, sedentariness and appetite regulation: pathways to obesity

2016

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Energy balance is not a simple algebraic sum of energy expenditure and energy intake as often depicted in communications. Energy balance is a dynamic process and there exist reciprocal effects between food intake and energy expenditure. An important distinction is that of metabolic and behavioural components of energy expenditure. These components not only contribute to the energy budget directly, but also by influencing the energy intake side of the equation. It has recently been demonstrated that resting metabolic rate is a potential driver of energy intake, and evidence is accumulating on the influence of physical activity (behavoiural energy expenditure) on mechanisms of satiety and appetite control. These effects are associated with changes in leptin and insulin sensitivity, and in the plasma levels of gastrointestinal peptides such as glucagon-like peptide-1, ghrelin and cholecystokinin. The influence of fat-free mass on energy expenditure and as a driver of energy intake directs attention to molecules emanating from skeletal tissue as potential appetite signals.Sedentariness (physical inactivity) is positively associated with adiposity and is proposed to be a source of overconsumption and appetite dysregulation. The molecular signals underlying these effects are not known but represent a target for research. Running title:Energy Balance, Body Composition and Appetite Regulation Key words:Appetite regulation, energy intake, fat-free mass, resting metabolic rate, sedentariness. ENERGY BALANCE REGULATION: A DYNAMIC RELATIONSHIP BETWEEN BIOLOGY AND BEHAVIOURWeight gain is often explained as a function energy balance, with sustained periods of excess energy intake over energy expenditure thought to promote the accumulation of adipose tissue. Unfortunately however system, in which reductions in energy intake, or increases in energy expenditure, automatically lead to energy deficit, and in turn, weight loss. This approach is simplistic and belies the complexity of energy balance regulation in humans in the current obesogenic environment. Furthermore, it ignores the potential for behavioral or biological adaptation to restore energy homeostasis during periods of energy deficit or surfeit (1). Rather than being static, the regulation of energy balance is a dynamic process in which perturbations to one component of energy balance may elicit biological and/or behavioral compensation in other components of the system. These auto-regulatory or compensatory responses act to minimize perturbations to energy homeostasis, in turn, body weight (1, 2). For example, it has been suggested that some individuals experience a compensatory reduction in resting energy expenditure, termed adaptive thermogenesis (3), following dietary (4, 5) and exercise-induced (6) weight loss. Compensation may also be behavioural in nature, with dietary (7, 8) and exercise-induced (9, 10) weight loss shown to result in increased fasting hunger (although such changes in subjective appetite do not always translate into changes in actual beha...

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“…Loss of metabolic capacity after mitochondrial damage is a major pathophysiological mechanism of myocardial dysfunction and cardiac failure [13]. At molecular level, AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis which is activated in conditions of energy depletion when there is an intracellular imbalance of high AMP and low ATP levels [14]. AMPK promotes metabolic recovery through activation of peroxisome proliferator-activated receptor γ co-activator α (PGC-1α), a nuclear transcriptional co-activator responsible for mitochondrial biogenesis [14–16].…”

Section: Introductionmentioning

confidence: 99%

“…At molecular level, AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis which is activated in conditions of energy depletion when there is an intracellular imbalance of high AMP and low ATP levels [14]. AMPK promotes metabolic recovery through activation of peroxisome proliferator-activated receptor γ co-activator α (PGC-1α), a nuclear transcriptional co-activator responsible for mitochondrial biogenesis [14–16]. Several experimental studies have demonstrated that aging-associated loss in AMPK activity may contribute to mitochondrial dysfunction in skeletal muscles and myocardium [17,18].…”

Section: Introductionmentioning

confidence: 99%

Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

Matsiukevich¹,

Piraino²,

Lahni³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Severity of multiple organ failure is significantly impacted by age and gender in patients with hemorrhagic shock. However, the molecular mechanisms underlying the enhanced organ injury are not fully understood. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of metabolic responses during stress. We investigated whether hemorrhage-induced myocardial injury is age and gender dependent and whether treatment with metformin, an AMPK activator, affords cardioprotective effects. C57/BL6 young (3–5 months) and mature (9–12 months) male and female mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with blood and Lactated Ringer’s solution. Vehicle-treated young and mature mice of both genders had a similar elevation of plasma inflammatory cytokines at 3 hours after resuscitation. However, vehicle-treated male mature mice experienced hemodynamic instability and higher myocardial damage than young male mice, as evaluated by echocardiography, histology and cardiovascular injury biomarkers. There was also a gender-dependent difference in cardiovascular injury in the mature group as vehicle-treated male mice exhibited more severe organ injury than female mice. At molecular analysis, vehicle-treated mature mice of both genders exhibited a marked downregulation of AMPKα activation and nuclear translocation of peroxisome proliferator-activated receptor γ co-activator α when compared with young mice. Treatment with metformin improved cardiovascular function and survival in mature animals of both genders. However, specific cardioprotective effects of metformin were gender-dependent. Metformin did not affect hemodynamic or inflammatory responses in young animals. Thus, our data suggest that targeting metabolic recovery with metformin may be a potential treatment approach in severe hemorrhage in adult population.

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Beyond Energy Homeostasis: the Expanding Role of AMP-Activated Protein Kinase in Regulating Metabolism

Cited by 74 publications

References 31 publications

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites

Energy balance, body composition, sedentariness and appetite regulation: pathways to obesity

Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

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