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