1. Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
- Author
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Yavari A, Stocker CJ, Ghaffari S, Wargent ET, Steeples V, Czibik G, Pinter K, Bellahcene M, Woods A, Martínez de Morentin PB, Cansell C, Lam BY, Chuster A, Petkevicius K, Nguyen-Tu MS, Martinez-Sanchez A, Pullen TJ, Oliver PL, Stockenhuber A, Nguyen C, Lazdam M, O'Dowd JF, Harikumar P, Tóth M, Beall C, Kyriakou T, Parnis J, Sarma D, Katritsis G, Wortmann DD, Harper AR, Brown LA, Willows R, Gandra S, Poncio V, de Oliveira Figueiredo MJ, Qi NR, Peirson SN, McCrimmon RJ, Gereben B, Tretter L, Fekete C, Redwood C, Yeo GS, Heisler LK, Rutter GA, Smith MA, Withers DJ, Carling D, Sternick EB, Arch JR, Cawthorne MA, Watkins H, and Ashrafian H
- Subjects
- Adiposity genetics, Adult, Aging pathology, Agouti-Related Protein metabolism, Animals, Arcuate Nucleus of Hypothalamus metabolism, Energy Metabolism genetics, Enzyme Activation, Feeding Behavior, Female, Heterozygote, Humans, Hyperphagia complications, Hyperphagia enzymology, Hyperphagia genetics, Hyperphagia pathology, Hypothalamus metabolism, Insulin metabolism, Male, Mice, Mitochondria metabolism, Mutation genetics, Neurons metabolism, Obesity blood, Obesity complications, Obesity pathology, Oxidative Phosphorylation, Receptors, Ghrelin metabolism, Ribosomes metabolism, Signal Transduction genetics, Transcriptome genetics, Up-Regulation genetics, AMP-Activated Protein Kinases metabolism, Insulin-Secreting Cells enzymology, Insulin-Secreting Cells pathology, Obesity enzymology
- 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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