PROTRH GENE TRANSCRIPTION AND BIOSYNTHESIS BY LEPTIN

作为对饥饿的适应性反应，下丘脑-垂体-甲状腺轴被下调。这至少部分是由于抑制了下丘脑中proTRH mRNA的表达，而这种抑制可以被瘦素逆转。有资料表明，瘦素对下丘脑室旁核(PVN)内TRH神经元的作用是通过参与下丘脑弓状核(AC)的间接途径实现的。这可能涉及从AC神经元释放神经肽，如NPY、MSH AgRP，这些神经肽是瘦素反应的，并投射到产生ProTRH的促垂体素神经元所在的PVN。然而，我们实验室最近的一项新工作有力地表明，TRH神经元也可能直接受到瘦素的调节，而不是中间途径。因此，在这项提议中，我们将确定瘦素对TRH神经元中PRTRH生命周期的作用所涉及的分子事件。作为一个模型系统，我们将利用我们建立的原代培养的下丘脑神经元，这些神经元表达高水平的内源性PRTRH和瘦素受体。有些方面将得到活体研究的证实。

As an adaptive response to starvation, the hypothalamic- pituitary-thyroid axis is down-regulated. This is caused, at least in part, by suppression of proTRH mRNA expression in the hypothalamus, which can be reversed by leptin. Some data suggest that the action of leptin on TRH neurons in the paraventricular nucleus (PVN) of the hypothalamus occur through an indirect pathway involving the arcuate nucleus (AC) of the hypothalamus. This may involve release of neuropeptides such as NPY, MSH AgRP from AC neurons that are leptin responsive and that project to the PVN where the hypophysiotropic neurons producing proTRH are located. However, a new line of work done recently in our laboratories strongly suggests that TRH neurons may also be regulated directly by leptin without intermediate pathways. Thus, in this proposal we will identify molecular events involved in the action of leptin on the proTRH life cycle in TRH neurons. As a model system we will utilize our established primary cultures of hypothalamic neurons that express high levels of endogenous proTRH and leptin receptors. Some aspects will be corroborated with in vivo studies.