VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA, United States.
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States.
Front Endocrinol (Lausanne). 2024 Jul 22;15:1432928. doi: 10.3389/fendo.2024.1432928. eCollection 2024.
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 (<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.
我们最近报道，一种新型嵌合肽（GEP44）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），可减少饮食诱导肥胖（DIO）大鼠的能量摄入和体重（BW）。我们假设 GEP44 通过 GLP-1R 依赖的机制减少能量摄入和 BW。为了验证这一假设，GLP-1R 小鼠和 GLP-1R 缺失（GLP-1R）小鼠在接受为期 3 天的载体期、3 天的药物治疗（5、10、20 或 50nmol/kg；GEP44 与选择性 GLP-1R 激动剂 exendin-4 比较）和 3 天的洗脱期之前，喂食高脂肪饮食 4 个月以引发饮食诱导性肥胖。每天测量能量摄入、BW、核心温度和活动。GEP44（10、20 和 50nmol/kg）在 3 天治疗后降低了雄性 DIO GLP-1R 小鼠的 BW，分别为-1.5±0.6、-1.3±0.4 和-1.9±0.4 克（<0.05），在雌性 GLP-1R 小鼠中也观察到类似的效果。在雄性和雌性 DIO GLP-1R 小鼠中，这些作用均不存在，表明 GLP-1R 信号传导有助于 GEP44 引起的 BW 减少。此外，GEP44 降低了雄性和雌性 DIO GLP-1R 小鼠的能量摄入，但 GEP44 在雄性中似乎在多个剂量下产生了更一致的效果。在 GLP-1R 小鼠中，仅在雄性中观察到 GEP44 对能量摄入的影响，而在雌性中则没有，这表明 GEP44 可能部分通过 GLP-1R 独立机制减少雄性的能量摄入。此外，GEP44 降低了雄性和雌性 GLP-1R 小鼠的核心温度和活动，表明它还可能降低能量消耗。最后，我们表明 GEP44 通过 GLP-1R 降低了 DIO 雄性和雌性小鼠的空腹血糖。综上所述，这些发现支持这样的假设，即嵌合肽 GEP44 通过 GLP-1R 依赖性机制减少雄性和雌性 DIO 小鼠的能量摄入、BW、核心温度和血糖水平。
