title: Loss of a neural AMP-activated kinase mimics the effects of elevated serotonin on fat, movement, and hormonal secretions.
abstract: AMP-activated protein kinase (AMPK) is an evolutionarily conserved master regulator of metabolism and a therapeutic target in type 2 diabetes. As an energy sensor, AMPK activity is responsive to both metabolic inputs, for instance the ratio of AMP to ATP, and numerous hormonal cues. As in mammals, each of two genes, aak-1 and aak-2, encode for the catalytic subunit of AMPK in C. elegans. Here we show that in C. elegans loss of aak-2 mimics the effects of elevated serotonin signaling on fat reduction, slowed movement, and promoting exit from dauer arrest. Reconstitution of aak-2 in only the nervous system restored wild type fat levels and movement rate to aak-2 mutants and reconstitution in only the ASI neurons was sufficient to significantly restore dauer maintenance to the mutant animals. As in elevated serotonin signaling, inactivation of AAK-2 in the ASI neurons caused enhanced secretion of dense core vesicles from these neurons. The ASI neurons are the site of production of the DAF-7 TGF-β ligand and the DAF-28 insulin, both of which are secreted by dense core vesicles and play critical roles in whether animals stay in dauer or undergo reproductive development. These findings show that elevated levels of serotonin promote enhanced secretions of systemic regulators of pro-growth and differentiation pathways through inactivation of AAK-2. As such, AMPK is not only a recipient of hormonal signals but can also be an upstream regulator. Our data suggest that some of the physiological phenotypes previously attributed to peripheral AAK-2 activity on metabolic targets may instead be due to the role of this kinase in neural serotonin signaling.
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Cunningham
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Aude D
authors.initials: AD
authors.lastname: Bouagnon
authors.affiliation: Instituto Nacional de Ciência e Tecnologia de Medicina Molecular, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Alexandre G
authors.initials: AG
authors.lastname: Barros
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.affiliation: Departamento de Física, Instituto de Ciências Exatas da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Leandro
authors.initials: L
authors.lastname: Malard
authors.affiliation: Instituto Nacional de Ciência e Tecnologia de Medicina Molecular, Faculdade de Medicina da Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: Romano-Silva
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, California, United States of America.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Ashrafi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics; D005502:Food; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth / Q000235:genetics; D061385:Insulins; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000096:biosynthesis; D008136:Longevity / Q000235:genetics; D009420:Nervous System / Q000166:cytology / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011972:Receptor, Insulin / Q000096:biosynthesis; D022142:Secretory Vesicles / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014365:Tryptophan Hydroxylase / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; C102095:DAF-7 protein, C elegans; D061385:Insulins; D008055:Lipids; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; C473608:daf-28 protein, C elegans; D012701:Serotonin; D014365:Tryptophan Hydroxylase; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; C510541:AAK-2 protein, C elegans; D055372:AMP-Activated Protein Kinases