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Cell Metab ; 23(5): 821-36, 2016 May 10.
Article in English | MEDLINE | ID: mdl-27133129

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.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Insulin-Secreting Cells/enzymology , Insulin-Secreting Cells/pathology , Obesity/enzymology , Adiposity/genetics , Adult , Aging/pathology , Agouti-Related Protein/metabolism , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Energy Metabolism/genetics , Enzyme Activation , Feeding Behavior , Female , Heterozygote , Humans , Hyperphagia/complications , Hyperphagia/enzymology , Hyperphagia/genetics , Hyperphagia/pathology , Hypothalamus/metabolism , Insulin/metabolism , Male , Mice , Mitochondria/metabolism , Mutation/genetics , Neurons/metabolism , Obesity/blood , Obesity/complications , Obesity/pathology , Oxidative Phosphorylation , Receptors, Ghrelin/metabolism , Ribosomes/metabolism , Signal Transduction/genetics , Transcriptome/genetics , Up-Regulation/genetics
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