Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
Yavari, A; Stocker, CJ; Ghaffari, S; et al.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; Ashrafian, H
Date: 28 April 2016
Article
Journal
Cell Metabolism
Publisher
Elsevier
Publisher DOI
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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 ...
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.
Institute of Biomedical & Clinical Science
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