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

Research output: Article

48 Citations (Scopus)


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 pages16
JournalCell Metabolism
Issue number5
Publication statusPublished - máj. 10 2016

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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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), 821-836.