Role of signal transducer and activator of transcription 3 in regulation of hypothalamic trh gene expression by leptin.
During starvation in rodents, the hypothalamic-pituitary-thyroid axis is down-regulated, resulting in low circulating thyroid hormone levels. This involves a reduction in hypothalamic TRH mRNA that is caused in part by a fall in serum leptin levels, which is sensed by neurons within the hypothalamus. The mechanism by which this regulation occurs is not fully understood. Here we show transfection data and in vivo evidence, suggesting that leptin can regulate trh gene expression via activation of intracellular signal transducer and activator of transcription 3 (STAT3) proteins in TRH neurons. In trh promoter assays using transfected cells, functional STAT3 proteins are required for maximal activation of the trh promoter by leptin. Consistent with this, the STAT3-binding site on the leptin receptor is also required for this regulation. Using double immunohistochemistry, we show that peripherally administered leptin rapidly stimulates STAT3 phosphorylation in approximately 40% of TRH neurons in the paraventricular nucleus of the hypothalamus (PVN) in rats. Detailed anatomical analyses reveal that the leptin-responsive TRH neurons are concentrated in the caudal region of the medial and periventricular parvocellular subnucleus of the PVN. Combined, our data show that only a subpopulation of TRH neurons in the PVN is leptin responsive and suggest that stimulation of hypothalamic trh gene expression by leptin involves activation of STAT3 and that this signaling pathway is important for regulation of the hypothalamic-pituitary-thyroid axis by leptin.
Huo
Lihong
L
Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Münzberg
Heike
H
Nillni
Eduardo A
EA
Bjørbaek
Christian
C
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007668:Kidney; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D020218:Response Elements / Q000235:genetics; D050796:STAT3 Transcription Factor; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D004268:DNA-Binding Proteins; C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; C515447:leptin receptor, mouse; D013973:Thyrotropin-Releasing Hormone