Cell Metabolism
Volume 23, Issue 5, 10 May 2016, Pages 821-836
Journal home page for Cell Metabolism

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

https://doi.org/10.1016/j.cmet.2016.04.003Get rights and content
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Highlights

  • An activating mutation of γ2 AMPK in mice causes obesity and impairs insulin secretion

  • This occurs in part due to augmentation of ghrelin signaling-dependent hyperphagia

  • Humans with the homologous γ2 mutation show key aspects of the murine phenotype

  • These findings have implications for therapeutic strategies that aim to activate AMPK

Summary

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.

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