The metabolic regulator PGC-1α directly controls the expression of the hypothalamic neuropeptide oxytocin.
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.
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
Janna
J
Blechman
Liat
L
Amir-Zilberstein
Amos
A
Gutnick
Shifra
S
Ben-Dor
Gil
G
Levkowitz
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D002461:Cell Line, Transformed; D047369:Chromatin Immunoprecipitation / Q000379:methods; D019295:Computational Biology; D004625:Embryo, Nonmammalian; D005215:Fasting / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010121:Oxytocin / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D015027:Zebrafish
D006360:Heat-Shock Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D010121:Oxytocin