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

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