Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.
Yavari A., Stocker CJ., Ghaffari S., Wargent ET., Steeples V., Czibik G., Pinter K., Bellahcene M., Woods A., Martínez de Morentin PB., Cansell C., Lam BY., Chuster A., Petkevicius K., Nguyen-Tu MS., Martinez-Sanchez A., Pullen TJ., Oliver PL., Stockenhuber A., Nguyen C., Lazdam M., O'Dowd JF., Harikumar P., Tóth M., Beall C., Kyriakou T., Parnis J., Sarma D., Katritsis G., Wortmann DD., Harper AR., Brown LA., Willows R., Gandra S., Poncio V., de Oliveira Figueiredo MJ., Qi NR., Peirson SN., McCrimmon RJ., Gereben B., Tretter L., Fekete C., Redwood C., Yeo GS., Heisler LK., Rutter GA., Smith MA., Withers DJ., Carling D., Sternick EB., Arch JR., Cawthorne MA., Watkins H., Ashrafian H.
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.