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. ; We thank: Sandra Stobrawa and colleagues (Genoway Lyon) for generating R299Q γ2 mice; families participating in the R302Q phenotyping study; Wellcome Trust Centre for Human Genetics HighThroughput Genomics Group (grant 090532/Z/09/Z) for sequencing data; Hermes Pardini for human biochemistry; Karen McGuire, Kate Thomson and Jessica Woodley (Oxford Medical Genetics Laboratories) for R302Q genotyping; Keith Burling (Core Biochemical Assay Laboratory Cambridge) and Tertius Hough (MRC, Harwell Oxford) for murine biochemistry; Paul Trayhurn for comments; and Parisa Yavari for artwork support. This work utilised Core Services supported by grants DK089503 (MNORC) and DK020572 (MDRC) of the NIH to the University of Michigan. C.B. is supported by a Diabetes UK RD Lawrence Fellowship (13/0004647). C.F. and B.G. are supported by the Hungarian National Brain Research Program. G.A.R. was supported by a Wellcome Trust Senior Investigator Award (WT098424AIA), MRC Programme Grant (MR/J0003042/1) and a Royal Society Wolfson Research Merit Award. A.Y. was funded by a Wellcome Trust Research Training Fellowship (086632/Z/08/Z) and is supported by the UK National Institute for Health Research. A.Y. (RE/08/004), H.W. and H.A. acknowledge support from the BHF Centre of Research Excellence, Oxford. This work was supported by a grant from the Wellcome Trust to L.K.H. (WT098012), and from the MRC to H.A. and H.W. (MR/K019023/1).