Effects of Exendin-4 Alone and With Peptide YY3-36 on Food Intake and Body Weight in Diet-Induced Obese Rats
Effects of Exendin-4 Alone and With Peptide YY3-36 on Food Intake and Body Weight in Diet-Induced Obese Rats
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DOI：
10.1038/oby.2010.136
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发表时间：
2011-01-01
期刊：
影响因子：
6.9
通讯作者：
Steenson, Sharalyn M.
中科院分区：
文献类型：
--
作者：
Reidelberger, Roger D.;Haver, Alvin C.;Steenson, Sharalyn M.
肥胖人群Roux-en-Y胃旁路手术（RYGB）后体重显著减轻与促消化肠激素胰高血糖素样肽-1（GLP-1）和肽YY 3 -36（PYY 3 -36）分泌增强相关。我们的目的是确定单独和与PYY 3 -36一起腹膜内（IP）输注GLP-1同系物毒蜥外泌肽-4的给药策略，其在饮食诱导的肥胖（DIO）大鼠中产生每日食物摄入量和体重的持续降低。我们在10周内测试了12种exendin-4策略。在黑暗期的第一个和最后3小时期间以15-20 pmol/h（0.15 nmol/kg/天）输注Exendin-4，导致每日摄食量持续减少24 +/- 1%，持续17天，体重降低7%。在单独的DIO大鼠组中，组合毒蜥外泌肽-4和PYY 3 -36的七种给药策略中没有一种产生类似的每日食物摄入减少>10天。在每个实验中，毒蜥外泌肽-4单独和与PYY 3 -36一起对食物摄入和体重的功效的随后下降表明可能的受体下调和对治疗的耐受性。然而，当效力丧失后停止给药1天时，每日摄食量显著增加。总之，这些结果表明：（i）低剂量毒蜥外泌肽-4的间歇IP输注可以在DIO大鼠中产生每日食物摄入和体重的相对延长的减少，（ii）毒蜥外泌肽-4和PYY 3 -36的共输注不会进一步延长该应答，和（iii）食欲产生机制的激活逐渐发生，以抵消单独的毒蜥外泌肽-4和PYY 3 -36对食物摄取和体重的抑制作用。
Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY3-36). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY3-36 that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 +/- 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY3-36 produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY3-36 on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY3-36 does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY3-36 on food intake and body weight.