We recently reported that a chimeric peptide (GEP44) targeting the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2- receptors decreased body weight (BW), energy intake, and core temperature in diet-induced obese (DIO) male and female mice. In the current study, we tested the hypothesis that the strong reduction in body weight in response to GEP44 is partially related to the stimulation of energy expenditure (EE). To test this, rats were maintained on a high fat diet (HFD) for at least 4 months to elicit DIO prior to undergoing a sequential 2-day vehicle period, 2-day GEP44 (50 nmol/kg) period, and a minimum 2-day washout period, and detailed measures of energy homeostasis. GEP44 (50 nmol/kg) reduced EE (indirect calorimetry), respiratory exchange ratio (RER), core temperature, activity, energy intake, and BW in male and female rats. As in our previous study in mice, GEP44 reduced BW in male and female HFD-fed rats by 3.8 ± 0.2% and 2.3 ± 0.4%, respectively. These effects appear to be mediated by increased lipid oxidation and reductions in energy intake as GEP44 reduced RER and cumulative energy intake in male and female HFD-fed rats. The strong reduction in body weight in response to GEP44 is related to a robust reduction in energy intake, but not to the stimulation of EE. The paradoxical finding that GEP44 reduced EE might be secondary to a reduction in diet-induced thermogenesis or might indicate an important mechanism to limit the overall efficacy of GEP44 to prevent further weight loss.

Keywords: GLP-1; PYY; iBAT; iWAT; multi-agonist; obesity.

我们最近报道了一种嵌合肽（GEP44），该肽靶向胰高血糖素样肽-1受体（GLP-1R）和神经肽Y1及Y2受体，在喂食高脂饮食诱导的肥胖雄性和雌性小鼠中降低了体重、能量摄入和核心体温。在当前的研究中，我们测试了假设GEP44引起的体重显著减少部分是由于刺激能量消耗（EE）。为此，实验大鼠被维持在一个高脂肪饮食上至少四个月以引发DIO状态，并随后经历了为期两天的载体时期、两天的GEP44 (50 nmol/kg) 时期和最少两天的清洗期，并详细测量了能量稳态。结果表明，GEP44 (50 nmol/kg) 在雄性和雌性大鼠中减少了EE（间接量热法）、呼吸商（RER）、核心体温、活动水平、能量摄入和体重。与我们在小鼠中的先前研究一致，在高脂饮食喂养的雄性和雌性大鼠中，GEP44分别使体重减少了3.8±0.2% 和 2.3±0.4%。这些效果似乎是由增加的脂肪氧化和减少的能量摄入介导的，因为GEP44在雄性和雌性高脂饮食喂养的大鼠中降低了RER和累计能量摄入。对GEP44响应产生的体重显著下降与能量摄入大幅降低有关，而不是由于EE的刺激导致。令人困惑的是，GEP44减少EE的现象可能是由饮食诱导产热减少引起的，也可能表明了限制GEP44整体有效性的关键机制以防止进一步减重。

关键词：GLP-1；PYY；iBAT；iWAT；多激动剂；肥胖。