Asunto(s)
Potenciales de Acción , Bloqueo Atrioventricular/etiología , Cardiomiopatías/complicaciones , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca , Proteínas Quinasas Activadas por AMP/genética , Adulto , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/fisiopatología , Bloqueo Atrioventricular/terapia , Cardiomiopatías/diagnóstico , Cardiomiopatías/enzimología , Cardiomiopatías/genética , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Predisposición Genética a la Enfermedad , Humanos , Masculino , Mutación , Fenotipo , Recurrencia , Síncope/etiología , Factores de TiempoRESUMEN
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.