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

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.

Graphical Abstract

Highlights

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

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

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

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

Abstract

AMPK is a promising therapeutic target for obesity. Yavari et al. reveal the potential consequences of chronic AMPK activation in mice carrying an activating γ2 mutation, which results in obesity, hyperphagia, and impaired insulin secretion. Increased adiposity and reduced β cell function are also observed in humans bearing this mutation.