Blüher Susann, Ziotopoulou Mary, Bullen John W, Moschos Stergios J, Ungsunan Linda, Kokkotou Efi, Maratos-Flier Eleftheria, Mantzoros Christos S
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Diabetes. 2004 Jan;53(1):82-90. doi: 10.2337/diabetes.53.1.82.
To elucidate mechanisms of melanocortin action, we investigated the effects of a melanocortin receptor agonist (melanotetan II [MTII]) in lean C57BL/6J and obese (DIO, ob/ob, UCP1-DTA) mice. MTII administration (100 microg q.i.d. i.p.) for 24 h results in similar weight loss but a more pronounced decrease of food intake in DIO mice. After 4 and 8 days of MTII treatment, however, the reduction in both food intake and body weight is more pronounced in DIO mice than in lean mice. MTII administration for 24 h prevents food deprivation-induced alterations in hypothalamic neuropeptide Y (NPY) and liver adiponectin receptor 1 and adiponectin receptor 2 mRNA expression, but does not alter hypothalamic mRNA expression of melanocortin 4 receptor or adiponectin serum and mRNA expression levels. NPY and agouti gene-related protein (AgRP) mRNA expression after 8 days of MTII is increased to levels comparable to pair-fed mice. In summary, 1) MTII is an effective treatment for obesity and related metabolic defects in leptin-resistant (DIO, UCP1-DTA) and leptin-sensitive (ob/ob) mouse models of obesity; 2) the effects of MTII on food intake and body weight are more pronounced in DIO mice than in lean mice; 3) the tachyphylactic effect after prolonged MTII administration appears to be, at least in part, caused by a compensatory upregulation of NPY and AgRP mRNA levels, whereas decreasing leptin levels may play a very minor role in mediating tachyphylaxis; and 4) alterations in adiponectin receptor mRNA expression after fasting or MTII treatment may contribute to altered insulin sensitivity and needs to be studied further.
为阐明黑皮质素的作用机制，我们研究了黑皮质素受体激动剂（melanotetan II [MTII]）对瘦型C57BL/6J小鼠和肥胖（饮食诱导肥胖、ob/ob、UCP1-DTA）小鼠的影响。腹腔注射MTII（100微克，每日4次）24小时导致饮食诱导肥胖小鼠体重减轻相似，但食物摄入量下降更为明显。然而，在MTII治疗4天和8天后，饮食诱导肥胖小鼠的食物摄入量和体重下降比瘦型小鼠更为显著。腹腔注射MTII 24小时可防止食物剥夺引起的下丘脑神经肽Y（NPY）以及肝脏脂联素受体1和脂联素受体2 mRNA表达的改变，但不会改变下丘脑黑皮质素4受体的mRNA表达或脂联素血清及mRNA表达水平。MTII治疗8天后，NPY和刺鼠基因相关蛋白（AgRP）的mRNA表达增加至与成对喂养小鼠相当的水平。总之，1）MTII是瘦素抵抗（饮食诱导肥胖、UCP1-DTA）和瘦素敏感（ob/ob）肥胖小鼠模型中肥胖及相关代谢缺陷的有效治疗方法；2）MTII对食物摄入量和体重的影响在饮食诱导肥胖小鼠中比瘦型小鼠更为显著；3）长期给予MTII后的快速耐受效应似乎至少部分是由NPY和AgRP mRNA水平的代偿性上调引起的，而瘦素水平降低在介导快速耐受中可能起非常小的作用；4）禁食或MTII治疗后脂联素受体mRNA表达的改变可能导致胰岛素敏感性改变，需要进一步研究。
