胰淀素通过MC4R介导小鼠采食、产热效应的研究
发布时间：2018-08-03 19:49
【摘要】：黑素皮质素4型受体(Melanocortin receptor-4,MC4R)作为调控动物脂肪储存和能量消耗的神经元受体,其活动与背肩胛棕色脂肪组织(Interscapular BAT,iBAT)产热密切相关。其中以MC4R敲除鼠表现的过度肥胖为典型特征。在抗肥胖药物临床应用中,胰淀素(Amylin)以其调节中枢神经系统能量代谢平衡的作用被广泛关注。近期研究中,MC4R被称作治疗肥胖症的潜在作用靶点,同时证明了 Amylin在机体能量代谢中起重要调控作用。本次研究以腹腔注射Amylin(50 μg/kg)及MC4R拮抗剂(SHU9119,50μg/kg)的C57BL/6小鼠为实验模型,通过对其采食量和背肩胛棕色脂肪处温度的测定;对C-Fos和MC4R神经元定位及共表达信息的免疫荧光技术检测;利用Western Blot技术检测Amylin对下丘脑及iBAT组织中pACC、pAMPK、pERK、UCP1及MC4R等蛋白表达变化的影响。结果表明,Amylin可显著降低禁食16h后小鼠的采食量(p0.01),且可显著促进iBAT温度升高及C-Fos与MC4R在下丘脑神经核团中的表达,同时提高共表达率;单独注射SHU9119未见明显变化,但联合注射SHU9119和Amylin后,可阻断由Amylin引起的抑制采食及iBAT温度升高的效应,并抑制下丘脑区域C-Fos与MC4R神经元共表达。另外,Amylin可显著增加下丘脑和iBAT中pACC、pAMPK、UCP1及MC4R的蛋白表达量(p0.01)。注射Amylin可促进下丘脑中pERK表达,且抑制iBAT中pERK表达。联合注射SHU9119和Amylin,可抑制由Amylin引起的pACC、pAMPK、pERK、UCP1及MC4R在下丘脑和iBAT中的表达,其中单独注射SHU9119未见明显变化。综上所述,通过腹腔注射Amylin,可促进C-Fos和MC4R在下丘脑中神经元中的表达,并显著抑制采食效应,促进iBAT温度升高。该调控过程与pACC、pAMPK、pERK信号通路及UCP1、MC4R密切相关。揭示了 Amylin和MC4R途径在调节动物摄食行为及产热上的作用及其相互关系。结果提示,Amylin调节摄食行为和温度升高的作用可部分受MC4R途径介导。为理解MC4R介导Amylin调控中枢产热通路及推动Amylin在治疗肥胖等疾病的应用中提供理论依据。
[Abstract]:Melanocortin receptor-4 (MC4R) is a neuronal receptor regulating fat storage and energy expenditure in animals. The activity of MC4R is closely related to heat production in Interscapular fat tissue (Interscapular bat). The MC4R knockout mice were characterized by obesity. In the clinical application of anti-obesity drugs, amylin (Amylin) has been widely concerned because of its role in regulating energy metabolism balance in central nervous system. Recent studies have identified MC4R as a potential target for the treatment of obesity and has demonstrated that Amylin plays an important role in regulating energy metabolism in the body. In this study, we used C57BL/6 mice injected intraperitoneally with Amylin (50 渭 g/kg) and MC4R antagonist (SHU9119 ~ 50 渭 g/kg) as experimental models. The effects of Amylin on the expression of pACC-pAMPKUCP1 and MC4R in hypothalamus and iBAT were detected by Western Blot technique. The results showed that Amylin could significantly decrease the feed intake of mice after fasting for 16 h (p0.01), and could significantly increase the temperature of iBAT and the expression of C-Fos and MC4R in hypothalamic nucleus, and increase the coexpression rate of C-Fos and MC4R in hypothalamic nucleus. But after combined injection of SHU9119 and Amylin, the inhibitory effect of Amylin on feeding and the increase of iBAT temperature were blocked, and the co-expression of C-Fos and MC4R neurons in hypothalamus was inhibited. In addition, Amylin significantly increased the expression of pACC-pAMPK-UCP1 and MC4R in hypothalamus and iBAT (p0.01). Injection of Amylin could promote the expression of pERK in hypothalamus and inhibit the expression of pERK in iBAT. Combined injection of SHU9119 and Amylincould inhibit the expression of pACC-pAMPKPERKUCP1 and MC4R in hypothalamus and iBAT, but SHU9119 alone did not change significantly. In conclusion, intraperitoneal injection of Amylincould promote the expression of C-Fos and MC4R in hypothalamic neurons, significantly inhibit the feeding effect and promote the rise of iBAT temperature. This regulation process is closely related to the pACC-pAMPKPERK signaling pathway and UCP1 MC4R. The effects of Amylin and MC4R pathway on the regulation of feeding behavior and heat production in animals and their relationship were revealed. The results suggest that the effects of Amylin on feeding behavior and temperature rise may be partly mediated by MC4R pathway. In order to understand MC4R mediated Amylin regulation of central heat production pathway and promote the application of Amylin in the treatment of obesity and other diseases to provide theoretical basis.
【学位授予单位】：内蒙古农业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S852.2
[Abstract]:Melanocortin receptor-4 (MC4R) is a neuronal receptor regulating fat storage and energy expenditure in animals. The activity of MC4R is closely related to heat production in Interscapular fat tissue (Interscapular bat). The MC4R knockout mice were characterized by obesity. In the clinical application of anti-obesity drugs, amylin (Amylin) has been widely concerned because of its role in regulating energy metabolism balance in central nervous system. Recent studies have identified MC4R as a potential target for the treatment of obesity and has demonstrated that Amylin plays an important role in regulating energy metabolism in the body. In this study, we used C57BL/6 mice injected intraperitoneally with Amylin (50 渭 g/kg) and MC4R antagonist (SHU9119 ~ 50 渭 g/kg) as experimental models. The effects of Amylin on the expression of pACC-pAMPKUCP1 and MC4R in hypothalamus and iBAT were detected by Western Blot technique. The results showed that Amylin could significantly decrease the feed intake of mice after fasting for 16 h (p0.01), and could significantly increase the temperature of iBAT and the expression of C-Fos and MC4R in hypothalamic nucleus, and increase the coexpression rate of C-Fos and MC4R in hypothalamic nucleus. But after combined injection of SHU9119 and Amylin, the inhibitory effect of Amylin on feeding and the increase of iBAT temperature were blocked, and the co-expression of C-Fos and MC4R neurons in hypothalamus was inhibited. In addition, Amylin significantly increased the expression of pACC-pAMPK-UCP1 and MC4R in hypothalamus and iBAT (p0.01). Injection of Amylin could promote the expression of pERK in hypothalamus and inhibit the expression of pERK in iBAT. Combined injection of SHU9119 and Amylincould inhibit the expression of pACC-pAMPKPERKUCP1 and MC4R in hypothalamus and iBAT, but SHU9119 alone did not change significantly. In conclusion, intraperitoneal injection of Amylincould promote the expression of C-Fos and MC4R in hypothalamic neurons, significantly inhibit the feeding effect and promote the rise of iBAT temperature. This regulation process is closely related to the pACC-pAMPKPERK signaling pathway and UCP1 MC4R. The effects of Amylin and MC4R pathway on the regulation of feeding behavior and heat production in animals and their relationship were revealed. The results suggest that the effects of Amylin on feeding behavior and temperature rise may be partly mediated by MC4R pathway. In order to understand MC4R mediated Amylin regulation of central heat production pathway and promote the application of Amylin in the treatment of obesity and other diseases to provide theoretical basis.
【学位授予单位】：内蒙古农业大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：S852.2
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