Loss of a neural AMP-activated kinase mimics the effects of elevated serotonin on fat, movement, and hormonal secretions

PLoS Genet. 2014 Jun 12;10(6):e1004394. doi: 10.1371/journal.pgen.1004394. eCollection 2014 Jun.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / enzymology*
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans Proteins / biosynthesis
  • Caenorhabditis elegans Proteins / genetics*
  • Energy Metabolism / genetics
  • Food
  • Gene Expression Regulation, Developmental
  • Genes, Helminth / genetics
  • Insulins
  • Lipid Metabolism / genetics*
  • Lipids / biosynthesis
  • Longevity / genetics
  • Nervous System / cytology
  • Nervous System / enzymology*
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA Interference
  • RNA, Small Interfering
  • Receptor, Insulin / biosynthesis
  • Secretory Vesicles / metabolism
  • Serotonin / metabolism*
  • Transforming Growth Factor beta / biosynthesis
  • Tryptophan Hydroxylase / genetics

Substances

  • Caenorhabditis elegans Proteins
  • DAF-7 protein, C elegans
  • Insulins
  • Lipids
  • RNA, Small Interfering
  • Transforming Growth Factor beta
  • daf-28 protein, C. elegans
  • Serotonin
  • Tryptophan Hydroxylase
  • Receptor, Insulin
  • Protein-Serine-Threonine Kinases
  • AAK-2 protein, C elegans
  • AMP-Activated Protein Kinases