The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity

Viollet, Benoı̂t; Andréelli, Fabrizio; Jørgensen, Sebastian Beck; Perrin, Christophe; Géloën, Alain; Flamez, Daisy; Mu, James; Lenzner, Claudia; Baud., Olivier; Bennoun, Myriam; Gomas, Emmanuel; Nicolas, Gaël; Wojtaszewski, Jørgen F.P.; Kahn, Axel; Carling, David; Schuit, Frans; Birnbaum, Morris J.; Richter, Erik A.; Burcelin, Rémy; Vaulont, Sophie

doi:10.1172/jci16567

Cited by 452 publications

(292 citation statements)

References 39 publications

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“…25,30,31 Generation and Genotyping of eAMPK -/-Mice AMPK-floxed mice were obtained from Dr Viollet at Cochin Institute (Paris, France). 32 We generated eAMPK -/-mice by crossing AMPKfloxed mice with Tie2-Cre mice on a C57BL/6 background. 24,33 The genotype of mice was confirmed by polymerase chain reaction using primers specific for the AMPKα 1 gene (5′-TATTGCTGCCATTAGG CTAC-3′ and 5′-GACCTGACAGAATAGGATATGCCCAACCTC-3′), the AMPKα 2 gene (5′-GCTTAGCACGTTACCCTGGATGG-3′ and 5′-GTTATCAGCCCAACTAATTACAC-3′), and the Tie2-Cre transgene (5′-GCGGTCTGGCAGTAAAAACTATC-3′ and 5′-GTGAAACAGCA TTGCTGTCACTT-3′).…”

Section: Animal Experimentsmentioning

confidence: 99%

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

Omura

Satoh

Kikuchi

et al. 2016

Circulation Research

108

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C ytokines/chemokines and growth factors regulate pulmonary endothelial function and influence the development of pulmonary arterial hypertension (PAH).1 PAH is characterized by pulmonary vascular remodeling and perivascular inflammation, leading to right ventricular (RV) failure and premature death. [2][3][4][5] Endothelial dysfunction is a crucial pathogenic status that triggers a variety of vascular disorders, such as PAH. 6,7 Endothelial dysfunction is also considered a key underlying feature in most forms of clinical and experimental PAH, which is enhanced by inflammatory cytokines/ chemokines and growth factors.1,8 Indeed, we experience rapid progression and worsening of PAH, especially when complicated with infectious diseases, such as pneumonia and catheter-related infection.8 Pulmonary endothelial dysfunction in patients with PAH enhances pulmonary vascular remodeling through impaired release of vasodilators, such as nitric oxide (NO) and prostacyclin. [9][10][11] AMP-activated protein kinase (AMPK) is a heterotrimeric complex consisting of a catalytic subunit α and 2 regulatory subunits β and γ, and it is expressed in various tissues and Molecular Medicine© 2016 American Heart Association, Inc. ). In contrast, development of hypoxia-induced PH was accelerated in eAMPK -/-mice compared with controls. Furthermore, the exacerbation of PH in eAMPK -/-mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxiainduced PH in mice. Conclusions:

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Section: Animal Experimentsmentioning

confidence: 99%

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

Omura

Satoh

Kikuchi

et al. 2016

Circulation Research

108

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“…However, just the global AMPKα2 KO fed under HFD [100] and the AMPKα2 KO in POMC neurons (POM-Cα2KO) fed under standard and HFD, display increased body weight and fat [72,99]. Contrarily, mice with targeted ablation of AMPKα2 in AgRP neurons (AgRPα2KO) have an age-dependent lean phenotype [72].…”

Section: Ghrelin and Hypothalamic Ampk: A Crucial Duo In Energy Balancementioning

confidence: 99%

“…In fact, the absence of marked alterations in terms of body weight and feeding in some of the AMPK KOs is probably related to compensation by the remaining catalytic subunits, i.e. in the AMPKα2 KO mice, AMPKα1 is upregulated [100]. Whatever the case, additional experiments are necessary, given the fact that it has been recently demonstrated that at least the obese phenotype in POMCα2 KO mice is not due to compensatory upregulation of AMPKα1 [72].…”

Section: Ghrelin and Hypothalamic Ampk: A Crucial Duo In Energy Balancementioning

confidence: 99%

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

Morentin

González

Saha

et al. 2011

Rev Endocr Metab Disord

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The AMP-activated protein kinase (AMPK) is the downstream constituent of a kinase cascade that acts as a sensor of cellular energy levels. Current data unequivocally indicate that hypothalamic AMPK plays a key role in the control of the whole body energy balance, by integrating peripheral signals, such as hormones and metabolites, with central signals, such as neuropeptides, and eliciting allostatic changes in energy homeostasis. Although the molecular details of these interactions are not fully understood, recent evidence has suggested that the interaction between AMPK with hypothalamic lipid metabolism and other metabolic sensors, such as the uncoupling protein 2 (UCP-2), the mammalian target of rapamycin (mTOR) and the deacetylase sirtuin 1 (SIRT1), may play a main role in the hypothalamic control of feeding and energy expenditure. Here, we summarize the role of hypothalamic AMPK as whole body energy gauge. Understanding this key molecule and especially its functions at central level may provide new therapeutic targets for the treatment of metabolic alterations and obesity.

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“…The combined systemic suppression of AMPKα1 and AMPKα2 dramatically impairs animal viability. Besides, systemic suppression of AMPKα1 has no detectable metabolic phenotype or any defect in glucose homeostasis whereas a deletion of AMPKα2 subunit results in insulinresistance associated with dramatic reduction in glycogen synthesis and insulin secretory defect leading to impaired glucose tolerance (Viollet et al 2003b;Viollet et al 2003a). Hence, specific activation of the AMPKα2 subunit activates glucose transport in mouse skeletal muscle (Musi et al 2001;Nakano et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…AMPKα2 −/− mice were generated by ubiquitous knockout of the corresponding gene in embryonic stem cells (ESC), using a previously-described protocol (Viollet et al 2003b) on a C57BL/6 background. Transgenic heterozygous hSOD1 G93A mice were bred on a C57BL/6 background to generate hSOD1 G93A mice and wild-type (WT) littermates.…”

Section: Generation Of Transgenic Micementioning

confidence: 99%

Early ALS-type gait abnormalities in AMP-dependent protein kinase-deficient mice suggest a role for this metabolic sensor in early stages of the disease

et al. 2015

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motoneurons. While the principal cause of the disease remains so far unknown, the onset and progression of the pathology are increasingly associated with alterations in the control of cell metabolism. On the basis of the well-known key roles of 5'-adenosine monophosphate-activated protein kinase (AMPK) in sensing and regulating the intracellular energy status, we hypothesized that mice with a genetic deletion of AMPK would develop locomotor abnormalities that bear similarity with those detected in the very early disease stage of mice carrying the ALS-associated mutated gene hSOD1(G93A). Using an automated gait analysis system (CatWalk), we here show that hSOD1(G93A) mice and age-matched mice lacking the neuronal and skeletal muscle predominant α2 catalytic subunit of AMPK showed an altered gait, clearly different from wild type control mice. Double mutant mice lacking AMPK α2 and carrying hSOD1(G93A) showed the same early gait abnormalities as hSOD1(G93A) mice over an age span of 8 to 16 weeks. Taken together, these data support the concept that altered AMPK function and associated bioenergetic abnormalities could constitute an important component in the early pathogenesis of ALS. Therapeutic interventions acting on metabolic pathways could prove beneficial on early locomotor deficits, which are sensitively detectable in rodent models using the CatWalk system.

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The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity

Cited by 452 publications

References 39 publications

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

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

Early ALS-type gait abnormalities in AMP-dependent protein kinase-deficient mice suggest a role for this metabolic sensor in early stages of the disease

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