Fekete Csaba, Sarkar Sumit, Rand William M, Harney John W, Emerson Charles H, Bianco Antonio C, Lechan Ronald M
Department of Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary 1083.
Endocrinology. 2002 Oct;143(10):3846-53. doi: 10.1210/en.2002-220338.
Because alpha-MSH has a potent stimulatory action on hypophysiotropic TRH synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), preventing the effects of fasting on the gene expression of the TRH prohormone (proTRH), we hypothesized that agouti-related protein (AGRP), a melanocortin receptor antagonist, may exert a central inhibitory action on these neurons. To test the hypothesis, the effects of intracerebroventricularly administered AGRP on circulating thyroid hormone levels and proTRH mRNA in the hypothalamic paraventricular nucleus (PVN) were compared with the effects of the recently described central inhibitor of the HPT axis, neuropeptide Y (NPY). AGRP administration increased food consumption and weight gain, suppressed circulating levels of thyroid hormones (T(3) and T(4)), and resulted in an inappropriately normal TSH. These alterations were associated with a significant suppression of proTRH mRNA in the PVN, indicating that AGRP infusion resulted in a state of central hypothyroidism. While similar observations were made in the NPY-infused animals, AGRP-treated animals had higher feeding efficiency, higher T(4) levels, and lower type 2 iodothyronine deiodinase levels in brown adipose tissue than NPY-infused animals. These data demonstrate that AGRP and NPY have a similarly potent inhibitory action on the proTRH gene expression of hypophysiotropic neurons, indicating that both AGRP and NPY may play a major role in the inhibition of the HPT axis during fasting.
由于α-促黑素细胞激素（alpha-MSH）对下丘脑室旁核（PVN）中合成促甲状腺激素释放激素（TRH）的促垂体神经元具有强大的刺激作用，可防止禁食对TRH前体激素（proTRH）基因表达的影响，我们推测刺鼠相关蛋白（AGRP），一种黑皮质素受体拮抗剂，可能对这些神经元发挥中枢抑制作用。为验证这一假设，将脑室内注射AGRP对循环甲状腺激素水平及下丘脑室旁核（PVN）中proTRH mRNA的影响，与最近描述的下丘脑-垂体-甲状腺（HPT）轴中枢抑制剂神经肽Y（NPY）的作用进行了比较。注射AGRP增加了食物摄入量和体重增加，抑制了甲状腺激素（T3和T4）的循环水平，并导致促甲状腺激素（TSH）异常正常。这些改变与PVN中proTRH mRNA的显著抑制相关，表明注入AGRP导致了中枢性甲状腺功能减退状态。虽然在注射NPY的动物中也有类似观察结果，但与注射NPY的动物相比，接受AGRP治疗的动物具有更高的进食效率、更高的T4水平以及棕色脂肪组织中更低的2型碘甲状腺原氨酸脱碘酶水平。这些数据表明，AGRP和NPY对促垂体神经元的proTRH基因表达具有同样强大的抑制作用，表明AGRP和NPY在禁食期间对HPT轴的抑制中可能都起主要作用。
