Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms.
Liraglutide, leptin and their combined effects on feeding: additive intake reduction through common intracellular signalling mechanisms.
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DOI：
10.1111/dom.12423
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Grill HJ
中科院分区：
文献类型：
--
作者：
Kanoski SE;Ong ZY;Fortin SM;Schlessinger ES;Grill HJ
胰高血糖素样肽-1受体（GLP-1 R）激动剂和瘦素各自发挥促胰岛素生成作用。在组合中，摄入抑制和体重减轻效果大于单独的治疗，但机制尚不清楚。在瘦型大鼠中检查了利拉鲁肽（一种长效GLP-1类似物）和瘦素联合给药（分别以低或中等剂量皮下（SC）或第三脑室给药）对累积摄入量、进食模式和下丘脑细胞内信号蛋白[磷酸化信号转导和转录激活因子-3（pSTAT 3）和蛋白酪氨酸磷酸酶-1B（PTP 1B）]表达的影响。利拉鲁肽（25μg/kg）和瘦素（0.75μg）低剂量联合给药可叠加性降低累积摄食量和体重，这一结果主要通过显著降低进餐频率介导，而这两种药物单独给药时均不存在。利拉鲁肽单独给药也可减少进食量;与瘦素联合给药时未增强该效应。分别检查了中等剂量的利拉鲁肽（75μg/kg）和瘦素（4μg），均降低了进餐频率、累积摄食量和体重;仅利拉鲁肽降低了进餐量。在组合中，这些剂量没有进一步增强任一单独治疗的致瘤作用。离体免疫印迹显示，在利拉鲁肽-瘦素共同治疗后，下丘脑组织中的pSTAT 3升高，其作用大于单独的瘦素治疗。此外，SC利拉鲁肽降低了PTP 1B（瘦素受体信号传导的负调节因子）的表达，揭示了利拉鲁肽-瘦素联合给药后pSTAT 3应答增强的潜在机制。总之，这些结果提供了利拉鲁肽-瘦素联合治疗后食物摄入量和体重累加性降低的新行为和分子机制。
Glucagon like peptide-1 receptor (GLP-1R) agonists and leptin each exert anorexigenic effects. In combination, the intake inhibitory and weight loss effects are greater than either treatment alone, however the mechanisms unclear. Effects of liraglutide (a long-acting GLP-1 analogue) and leptin co-treatment, delivered in low or moderate doses subcutaneously (SC) or to the 3rd ventricle respectively, on cumulative intake, meal patterns, and hypothalamic expression of intracellular signaling proteins [phosphorylated signal transducer and activator of transcription-3 (pSTAT3) and protein tyrosine phosphatase-1B (PTP1B)] were examined in lean rats. A low-dose combination of liraglutide (25μg/kg) and leptin (0.75μg) additively reduced cumulative food intake and body weight, a result mediated predominantly through a significant reduction in meal frequency that was not present with either drug alone. Liraglutide treatment alone also reduced meal size; an effect not enhanced with leptin co-administration. Moderate doses of liraglutide (75μg/kg) and leptin (4μg) examined separately each reduced meal frequency, cumulative food intake, and body weight; only liraglutide reduced meal size. In combination these doses did not further enhance the anorexigenic effects of either treatment alone. Ex vivo immunoblot showed elevated pSTAT3 in hypothalamic tissue following liraglutide-leptin co-treatment, an effect greater than leptin treatment alone. In addition, SC liraglutide reduced expression of PTP1B (a negative regulator of leptin receptor signaling), revealing a potential mechanism for the enhanced pSTAT3 response following liraglutide-leptin co-administration. Collectively, these results provide novel behavioral and molecular mechanisms underlying the additive reduction in food intake and body weight following liraglutide-leptin combination treatment.
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影响因子：
120.7
作者：
Flegal, Katherine M.;Carroll, Margaret D.;Curtin, Lester R.
通讯作者：
Curtin, Lester R.
DOI：
10.1523/jneurosci.3262-11.2011
发表时间：
2011-10-12
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dossat AM;Lilly N;Kay K;Williams DL
通讯作者：
Williams DL
DOI：
10.1006/bbrc.2000.2288
发表时间：
2000-03-16
影响因子：
3.1
作者：
Goldstone, AP;Morgan, I;Bloom, SR
通讯作者：
Bloom, SR
DOI：
10.1152/ajpregu.1998.275.1.r180
发表时间：
1998-07-01
影响因子：
2.8
作者：
Kahler, A;Geary, N;Langhans, W
通讯作者：
Langhans, W
DOI：
10.1152/ajpregu.1998.275.1.r174
发表时间：
1998-07-01
影响因子：
2.8
作者：
Flynn, MC;Scott, TR;Plata-Salamán, CR
通讯作者：
Plata-Salamán, CR