Blechman, J., Amir-Zilberstein, L., Gutnick, A., Ben-Dor, S., and Levkowitz, G. (2011) The Metabolic Regulator PGC-1α Directly Controls the Expression of the Hypothalamic Neuropeptide Oxytocin. The Journal of neuroscience : the official journal of the Society for Neuroscience. 31(42):14835-14840.
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.