The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin
- Authors
- Blechman, J., Amir-Zilberstein, L., Gutnick, A., Ben-Dor, S., and Levkowitz, G.
- ID
- ZDB-PUB-111027-54
- Date
- 2011
- Source
- 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
- Keywords
- none
- 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
- PubMed
- 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.