The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin

Blechman, J., Amir-Zilberstein, L., Gutnick, A., Ben-Dor, S., and Levkowitz, G.
The Journal of neuroscience : the official journal of the Society for Neuroscience   31(42): 14835-14840 (Journal)
Registered Authors
Amir-Zilberstein, Liat, Blechman, Janna, Gutnick, Amos, Levkowitz, Gil
MeSH Terms
  • Analysis of Variance
  • Animals
  • Animals, Genetically Modified
  • Cell Line, Transformed
  • Chromatin Immunoprecipitation/methods
  • Computational Biology
  • Embryo, Nonmammalian
  • Fasting/physiology
  • Feeding Behavior/drug effects
  • Feeding Behavior/physiology
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Expression Regulation, Developmental/genetics
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Heat-Shock Proteins/genetics
  • Heat-Shock Proteins/metabolism*
  • Humans
  • Hypothalamus/cytology*
  • Hypothalamus/metabolism
  • Male
  • Mice
  • Neurons/drug effects
  • Neurons/metabolism*
  • Oligodeoxyribonucleotides, Antisense/pharmacology
  • Oxytocin/genetics
  • Oxytocin/metabolism*
  • RNA, Messenger
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Transfection/methods
  • Zebrafish
22016516 Full text @ J. Neurosci.

The transcriptional coactivator PGC-1α is a key regulator of cellular energy expenditure in peripheral tissues. Recent studies report that PGC-1α-null mice develop late-onset obesity and that the neuronal inactivation of PGC-1α causes increased food intake. However, the exact role of PGC-1α in the CNS remains unclear. Here we show that PGC-1α directly regulates the expression of the hypothalamic neuropeptide oxytocin, a known central regulator of appetite. We developed a unique genetic approach in the zebrafish, allowing us to monitor and manipulate PGC-1α activity in oxytocinergic neurons. We found that PGC-1α is coexpressed with oxytocin in the zebrafish hypothalamus. Targeted knockdown of the zebrafish PGC-1α gene activity caused a marked decrease in oxytocin mRNA levels and inhibited the expression of a transgenic GFP reporter driven by the oxytocin promoter. The effect of PGC-1α loss of function on oxytocin gene activity was rescued by tissue-specific re-expression of either PGC-1α or oxytocin precursor in zebrafish oxytocinergic neurons. PGC-1α activated the oxytocin promoter in a heterologous cell culture system, and overexpression of PGC-1α induced ectopic expression of oxytocin in muscles and neurons. Finally, PGC-1α forms an in vivo complex with the oxytocin promoter in fed but not fasted animals. These findings demonstrate that PGC-1α is both necessary and sufficient for the production of oxytocin, implicating hypothalamic PGC-1α in the direct activation of a hypothalamic hormone known to control energy intake.

Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes