Abstract:
We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by -1.5 ± 0.6, -1.3 ± 0.4 and -1.9 ± 0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.
摘要:
我们最近报道了一种靶向胰高血糖素样肽-1受体(GLP-1R)和神经肽Y1-和Y2受体(Y1R和Y2R)的新型嵌合肽(GEP44)降低了饮食诱导的肥胖(DIO)大鼠的能量摄入和体重(BW)。我们假设GEP44主要通过GLP-1R依赖性机制减少能量摄入和BW。为了检验这个假设,GLP-1R+/+小鼠和GLP-1R无效(GLP-1R-/-)小鼠在连续3天的载体期之前,给予高脂肪饮食4个月以引发饮食诱导的肥胖。3天药物治疗(5、10、20或50nmol/kg;GEP44与选择性GLP-1R激动剂,exendin-4)和3天的冲洗。能量摄入,BW,每天测量核心温度和活动。GEP44(10、20和50nmol/kg)在DIO雄性GLP-1R+/+小鼠治疗3天后可降低BW-1.5±0.6、-1.3±0.4和-1.9±0.4克,分别为(P<0.05),在雌性GLP-1R+/+小鼠中观察到类似的效果。这些作用在雄性和雌性DIOGLP-1R-/-小鼠中不存在,表明GLP-1R信号传导有助于GEP44引起的BW降低。Further,GEP44降低了雄性和雌性DIOGLP-1R+/+小鼠的能量摄入,但是GEP44似乎在男性的多剂量中产生更一致的效果。在GLP-1R-/-小鼠中,GEP44对能量摄入的影响仅在男性而非女性中观察到,这表明GEP44可能会减少能量摄入,在某种程度上,通过男性的GLP-1R独立机制。此外,GEP44降低了雄性和雌性GLP-1R+/+小鼠的核心温度和活性,表明它也可以降低能量消耗。最后,我们显示GEP44通过GLP-1R降低DIO雄性和雌性小鼠的空腹血糖。一起,这些发现支持嵌合肽,GEP44,减少能量摄入,BW,核心温度,雄性和雌性DIO小鼠中的葡萄糖水平主要通过GLP-1R依赖性机制。