The metabolic regulator PGC-1? directly controls the expression of the hypothalamic neuropeptide oxytocin.

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

SUBMITTER: Blechman J 

PROVIDER: S-EPMC6623572 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature