GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway
GDF15 enhances body weight and adiposity reduction in obese mice by leveraging the leptin pathway
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DOI：
10.1016/j.cmet.2023.06.009
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发表时间：
2023-08-08
期刊：
影响因子：
29
通讯作者：
Tsai, Vicky Wang-Wei
中科院分区：
文献类型：
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作者：
Breit, Samuel N.;Manandhar, Rakesh;Tsai, Vicky Wang-Wei
GDF15通过其受体胶质源性神经营养因子受体α样受体表达的后脑最后区(AP)和孤束核(NTS)神经元来调节其厌食效应。GDF15的作用可能与肥胖引起的其他食欲调节因子相互作用，如瘦素。在这里，我们报告，在高脂饮食诱导肥胖(HFD)的小鼠中，联合应用GDF15和瘦素比单独使用任何一种治疗方法都能显著减少体重和肥胖，这表明GDF15和瘦素之间的作用。此外，肥胖、瘦素缺乏的ob/ob小鼠对GDF15的反应较差，而使用竞争性瘦素拮抗剂治疗的正常小鼠也是如此。GDF15和瘦素在HFD小鼠中诱导更多的后脑神经元激活，而不是单独治疗。我们报道了GFra和Lepr表达神经元之间的广泛联系，并发现Lepr在NTS中被敲除，从而减少了GDF15介导的AP神经元的激活。总体而言，这些发现表明，后脑中的瘦素信号通路增加了GDF15‘S的代谢活动。
GDF15 regulates its anorexic effects through the hindbrain area postrema (AP) and nucleus of the solitary tract (NTS) neurons where its receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), is ex-pressed. The actions of GDF15 may interact with other appetite regulators elevated in obesity, such as leptin. Here, we report that in mice with high-fat-diet-induced obesity (HFD), the combined infusion of GDF15 and leptin causes significantly greater weight and adiposity loss than either treatment alone, indicating potenti-ation between GDF15 and leptin. Furthermore, obese, leptin-deficient ob/ob mice are less responsive to GDF15, as are normal mice treated with a competitive leptin antagonist. GDF15 and leptin induce more hind -brain neuronal activation in HFD mice than either treatment alone does. We report extensive connections between GFRAL-and LepR-expressing neurons and find LepR knockdown in the NTS to reduce the GDF15-mediated activation of AP neurons. Overall, these findings suggest that leptin signaling pathways in the hindbrain increase GDF15's metabolic actions.