Goldberg Matvey, Blevins James E, Wolden-Hanson Tami, Elfers Clinton T, Chichura Kylie S, Ashlaw Emily F, den Hartigh Laura J, Roth Christian L, Doyle Robert P
VA Puget Sound Health Care System, Office of Research and Development Medical Research Service, Department of Veterans Affairs Medical Center, Seattle, WA 98108, USA.
Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Int J Mol Sci. 2025 Mar 26;26(7):3032. doi: 10.3390/ijms26073032.
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.
我们最近报道，一种靶向胰高血糖素样肽-1受体（GLP-1R）以及神经肽Y1和Y2受体的嵌合肽（GEP44）可降低饮食诱导肥胖（DIO）的雄性和雌性小鼠的体重（BW）、能量摄入和核心体温。在当前研究中，我们检验了这样一个假设，即GEP44引起的体重显著下降部分与能量消耗（EE）的刺激有关。为了验证这一点，在进行连续2天的赋形剂处理期、2天的GEP44（50 nmol/kg）处理期和至少2天的洗脱期以及详细的能量稳态测量之前，先让大鼠食用高脂肪饮食（HFD）至少4个月以诱发DIO。GEP44（50 nmol/kg）降低了雄性和雌性大鼠的EE（间接测热法）、呼吸交换率（RER）、核心体温、活动量、能量摄入和BW。与我们之前在小鼠中的研究一样，GEP44使雄性和雌性HFD喂养大鼠的BW分别降低了3.8±0.2%和2.3±0.4%。这些作用似乎是由脂质氧化增加和能量摄入减少介导的，因为GEP44降低了雄性和雌性HFD喂养大鼠的RER和累积能量摄入。GEP44引起的体重显著下降与能量摄入的显著减少有关，而与EE的刺激无关。GEP44降低EE这一矛盾的发现可能是饮食诱导产热减少的继发结果，或者可能表明存在一种重要机制来限制GEP44预防进一步体重减轻的总体功效。
