Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function

Arash Yavari, Claire J. Stocker, Sahar Ghaffari, Edward T. Wargent, Violetta Steeples, Gabor Czibik, Katalin Pinter, Mohamed Bellahcene, Angela Woods, Pablo B. Martínez de Morentin, Céline Cansell, Brian Y. H. Lam, André Chuster, Kasparas Petkevicius, Marie-Sophie Nguyen-Tu, Aida Martinez-Sanchez, Timothy J. Pullen, Peter L. Oliver, Alexander Stockenhuber, Chinh NguyenMerzaka Lazdam, Jacqueline F. O'Dowd, Parvathy Harikumar, Mónika Tóth, Craig Beall, Theodosios Kyriakou, Julia Parnis, Dhruv Sarma, George Katritsis, Diana D. J. Wortmann, Andrew R. Harper, Laurence A. Brown, Robin Willows, Silvia Gandra, Victor Poncio, Márcio J. de Oliveira Figueiredo, Nathan R. Qi, Stuart N. Peirson, Rory J. McCrimmon, Balázs Gereben, László Tretter, Csaba Fekete, Charles Redwood, Giles S. H. Yeo, Lora K. Heisler, Guy A. Rutter, Mark A. Smith, Dominic J. Withers, David Carling, Eduardo B. Sternick, Jonathan R. S. Arch, Michael A. Cawthorne, Hugh Watkins, Houman Ashrafian* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)821-836
Number of pages17
JournalCell Metabolism
Issue number5
Early online date28 Apr 2016
Publication statusPublished - 10 May 2016

Bibliographical note

We thank Sandra Stobrawa and colleagues (Genoway Lyon) for generating R299Q γ2 mice; families participating in the R302Q phenotyping study; Wellcome Trust Centre for Human Genetics High-Throughput Genomics Group (grant 090532/Z/09/Z) for sequencing data; Hermes Pardini for human biochemistry; Karen McGuire, Kate Thomson, and Jessica Woodley (Oxford Medical Genetics Laboratories) for R302Q genotyping; Keith Burling (Core Biochemical Assay Laboratory Cambridge) and Tertius Hough (MRC, Harwell Oxford) for murine biochemistry; Paul Trayhurn for comments; and Parisa Yavari for artwork support. This work utilized Core Services supported by grants DK089503 (MNORC) and DK020572 (MDRC) of the NIH to the University of Michigan. C.B. is supported by a Diabetes UK RD Lawrence Fellowship (13/0004647). C.F. and B.G. are supported by the Hungarian National Brain Research Program. L.K.H. is supported by the Wellcome Trust (WT098012) and BBSRC (BB/K001418/1). G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Programme Grant (MR/J0003042/1), and a Royal Society Wolfson Research Merit Award. A.Y. was funded by a Wellcome Trust Research Training Fellowship (086632/Z/08/Z) and is supported by the UK National Institute for Health Research. A.Y. (RE/08/004), H.W., and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. This work was supported by a grant from the MRC to H.A. and H.W. (MR/K019023/1).
This paper is dedicated to the memory of the late Professor Michael A.


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