Korner J, Wissig S, Kim A, Conwell I M, Wardlaw S L
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA.
J Neuroendocrinol. 2003 Dec;15(12):1116-21. doi: 10.1111/j.1365-2826.2003.01113.x.
The hypothalamic melanocortin system regulates feeding in part through interaction of the appetite stimulating peptide, agouti-related protein (AGRP), and the anorectic peptide, alpha-melanocyte stimulating hormone, a peptide derived from the pro-opiomelanocortin (POMC) polyprotein. Central administration of AGRP induces hyperphagia and increased gain in body weight in rodents, but may also exert metabolic effects even when hyperphagia is prevented. In the present studies, the effects of AGRP on hypothalamic neuropeptide gene expression and metabolism were examined in the rat. Central administration of AGRP for 3- and 7-day periods resulted in hyperphagia, increased body weight and increased plasma leptin and insulin concentrations compared to saline-injected controls. Hypothalamic concentrations of Pomc mRNA were also increased by 27% and 44% (in 3- and 7-day experiments, respectively). The hypothalamic concentration of Agrp mRNA was unchanged after 3 days, but was significantly decreased by 33% after 7 days of AGRP infusion. To determine if these changes were dependent upon AGRP-induced hyperphagia, pair-fed rats with restricted food intake receiving central administration of AGRP were also studied. In the absence of hyperphagia, intracerebralventricular administration of AGRP caused significant increases in plasma leptin and insulin concentrations (two-fold and 1.5-fold, respectively) and fat pad mass. A significant increase in hypothalamic Pomc mRNA concentrations was not detected in pair-fed rats. In contrast, Agrp mRNA concentrations remained suppressed by 45% in the pair-fed group after 7 days of AGRP infusion despite equal body weight compared to saline controls. The ratio of hypothalamic Pomc to Agrp mRNA was elevated two-fold in ad libitum and pair-fed AGRP-injected rats, which is consistent with increased stimulation of central melanocortin signalling pathways. Thus, central administration of AGRP exerts changes in hypothalamic neuropeptide gene expression and metabolic effects that are independent of the effects on food intake and body weight.
下丘脑黑素皮质素系统部分通过食欲刺激肽刺鼠相关蛋白（AGRP）与厌食肽α-黑素细胞刺激素（一种源自阿黑皮素原（POMC）多蛋白的肽）的相互作用来调节进食。向啮齿动物中枢给予AGRP会诱导食欲亢进并增加体重，但即使在防止食欲亢进的情况下也可能产生代谢效应。在本研究中，研究了AGRP对大鼠下丘脑神经肽基因表达和代谢的影响。与注射生理盐水的对照组相比，连续3天和7天向中枢给予AGRP导致食欲亢进、体重增加以及血浆瘦素和胰岛素浓度升高。下丘脑Pomc mRNA浓度在3天和7天的实验中也分别增加了27%和44%。AGRP输注3天后，下丘脑Agrp mRNA浓度未发生变化，但输注7天后显著降低了33%。为了确定这些变化是否依赖于AGRP诱导的食欲亢进，还研究了食物摄入量受限且接受中枢给予AGRP的配对喂养大鼠。在没有食欲亢进的情况下，脑室内给予AGRP导致血浆瘦素和胰岛素浓度显著升高（分别为两倍和1.5倍）以及脂肪垫质量增加。在配对喂养的大鼠中未检测到下丘脑Pomc mRNA浓度有显著增加。相反，尽管与生理盐水对照组体重相同，但在AGRP输注7天后，配对喂养组的Agrp mRNA浓度仍被抑制了45%。在自由进食和配对喂养的AGRP注射大鼠中，下丘脑Pomc与Agrp mRNA的比值升高了两倍，这与中枢黑素皮质素信号通路刺激增加一致。因此，中枢给予AGRP会引起下丘脑神经肽基因表达的变化和代谢效应，这些效应独立于对食物摄入和体重的影响。
