title: Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
abstract: Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.
authors.affiliation: Experimental Therapeutics, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. Electronic address: arash.yavari@well.ox.ac.uk.
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authors.affiliation: The Buckingham Institute for Translational Medicine, University of Buckingham, Buckingham MK18 1EG, UK.
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authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors.affiliation: The Buckingham Institute for Translational Medicine, University of Buckingham, Buckingham MK18 1EG, UK.
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authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB25 2ZD, UK.
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authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
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authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
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authors.affiliation: The Buckingham Institute for Translational Medicine, University of Buckingham, Buckingham MK18 1EG, UK.
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authors.affiliation: Experimental Therapeutics, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Experimental Therapeutics, Clinical Science Group, New Medicines, UCB Pharma S.A., Slough, Berkshire SL1 3WE, UK. Electronic address: houman.ashrafian@cardiov.ox.ac.uk.
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mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics; D000328:Adult; D000375:Aging / Q000473:pathology; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D004789:Enzyme Activation; D005247:Feeding Behavior; D005260:Female; D006579:Heterozygote; D006801:Humans; D006963:Hyperphagia / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D010085:Oxidative Phosphorylation; D054440:Receptors, Ghrelin / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D054369:Agouti-Related Protein; D007328:Insulin; D054440:Receptors, Ghrelin; D055372:AMP-Activated Protein Kinases