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

Arash Yavari (Lead / Corresponding author), 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 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

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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.

Original languageEnglish
Pages (from-to)821-835
Number of pages16
JournalCell Metabolism
Volume23
Issue number5
Early online date28 Apr 2016
DOIs
Publication statusPublished - 10 May 2016

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    Yavari, A., Stocker, C. J., Ghaffari, S., Wargent, E. T., Steeples, V., Czibik, G., Pinter, K., Bellahcene, M., Woods, A., Martínez de Morentin, P. B., Cansell, C., Lam, B. Y. H., Chuster, A., Petkevicius, K., Nguyen-Tu, M-S., Martinez-Sanchez, A., Pullen, T. J., Oliver, P. L., Stockenhuber, A., ... Ashrafian, H. (2016). Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function. Cell Metabolism, 23(5), 821-835. https://doi.org/10.1016/j.cmet.2016.04.003