Maekawa F, Fujiwara K, Kohno D, Kuramochi M, Kurita H, Yada T
Department of Physiology, Division of Integrative Physiology, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan.
J Neuroendocrinol. 2006 Oct;18(10):748-56. doi: 10.1111/j.1365-2826.2006.01470.x.
The present study aimed to examine whether hyperphagia, which is frequently observed in type 1 diabetic patients and model animals, also occurs in type 2 diabetic Goto-Kakizaki (GK) rats and, if so, to explore underlying abnormalities in the hypothalamus. GK rats at postnatal weeks 6-12, compared to control Wistar rats, exhibited hyperphagia, hyperglycaemia, hyperleptinemia and increased visceral fat accumulation, whereas body weight was unaltered. The ability of leptin to suppress feeding was reduced in GK rats compared to Wistar rats of these ages. In GK rats, leptin-induced phosphorylation of signal transducer and activator of transcription 3 was significantly reduced in the cells of the hypothalamic arcuate nucleus (ARC), but not of the ventromedial hypothalamus, whereas the mRNA level of functional leptin receptor was unaltered. By real-time polymerase chain reaction and in situ hybridisation, mRNA levels of neuropeptide Y, but not pro-opiomelanocortin and galanin-like peptide, were significantly increased in the ARC of GK rats at 11 weeks, but not 26 weeks. Following i.c.v. injection of a NPY Y1 antagonist, 1229U91, the amount of food intake in GK rats was indistinguishable from that in Wistar rats, thus eliminating the hyperphagia of GK rats. These results demonstrate that young adult GK rats display hyperphagia in association with leptin resistance and increased NPY mRNA level in the ARC.
本研究旨在探讨在1型糖尿病患者和模型动物中常见的食欲亢进现象是否也会出现在2型糖尿病Goto-Kakizaki（GK）大鼠中，若存在，则探究下丘脑潜在的异常情况。与对照Wistar大鼠相比，出生后6 - 12周的GK大鼠表现出食欲亢进、高血糖、高瘦素血症和内脏脂肪堆积增加，而体重未改变。与这些年龄段的Wistar大鼠相比，GK大鼠中瘦素抑制进食的能力降低。在GK大鼠中，下丘脑弓状核（ARC）细胞中瘦素诱导的信号转导和转录激活因子3的磷酸化显著降低，但腹内侧下丘脑细胞中未降低，而功能性瘦素受体的mRNA水平未改变。通过实时聚合酶链反应和原位杂交，11周龄而非26周龄的GK大鼠ARC中神经肽Y（NPY）的mRNA水平显著升高，而阿黑皮素原和甘丙肽样肽的mRNA水平未升高。脑室内注射NPY Y1拮抗剂1229U91后，GK大鼠的食物摄入量与Wistar大鼠无差异，从而消除了GK大鼠的食欲亢进。这些结果表明，年轻成年GK大鼠表现出食欲亢进，伴有瘦素抵抗和ARC中NPY mRNA水平升高。
